Free Pharmaceutical Books

Robustness of Analytical Chemical Methods and Pharmaceutical Technological Products

2008-12-22T09:26:00.002+05:30

Hardbound. In analytical chemistry and pharmaceutical technology attention is increasingly focussed on improving the quality of methods and products. This book aims at fostering the awareness of the potential of existing mathematical and statistical methods to improve this quality. It provides procedures and ideas on how to make a product or a method less sensitive to small variations in influencing factors. Major issues covered are robustness and stability improvement and ruggedness testing. General strategies and a theoretical introduction to these methods are described, and thorough overviews of methods used in both application areas and descriptions of practical applications are given.

Features of this book:

• Gives a good overview of mathematical and statistical methods used in two application areas, i.e. pharmaceutical technology and analytical chemistry

• Illustrates the different approaches available to attain robustness

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Formulation design of oxcarbazepine fast-release tablets prepared by melt granulation technique

2008-12-20T12:51:00.001+05:30

This work describes a melt granulation technique to improve the dissolution characteristics of a poorly water-soluble drug, oxcarbazepine. Melt granulation technique is a process by which pharmaceutical powders are efficiently agglomerated by a meltable binder. The advantage of this technique compared to conventional granulation is that no water or organic solvents are needed. Because there is no drying step, the process is less time consuming and uses less energy than wet granulation. In particular, the granules containing oxcarbazepine were prepared using polyethylene glycol (PEG) 4000 as a melting binder and lactose monohydrate as a hydrophilic filler. The potential of the intragranular addition of starch as a dissolution enhancer and a disintegrative agent was also evaluated. After analysis of their solid state was performed by means of x-ray powder diffraction (XRD), the granules were characterized from technological and dissolution point of view. The subsequent step comprised of the preparation and evaluation of the tablets, including the effect of the extragranular introduction of starch. Besides the remarkable enhancement of drug dissolution rate of the granulates in comparison to physical mixtures and pure drug, no significant differences were found between the dissolution profiles of the granulates containing lactose or starch. However, the difficult disintegration and bad dissolution performance of the tablets not containing intragranular starch so it is necessary to add disintegrant in the granulating mixture. Moreover, the extragranular addition of a small amount of starch gave rise to further amelioration of the disintegration and dissolution performances.

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Solubility enhancement and development of dispersible tablet of meloxicam

2008-12-20T12:47:00.000+05:30

The present research work investigates enhancement of dissolution profile of meloxicam using solid dispersion (SD) with various polymers. The work also describes the formulation of dispersible tablet (DT) and effervescent tablet of meloxicam. PEG 6000, PEG 8000, PEG 20000, Lutrol F-127, and β-cyclodextrin were selected for the preparation of SD. The SDs were prepared by melting and solvent evaporation methods. Dissolution studies were performed for plain meloxicam, SDs, and tablet formulations. Infrared spectroscopy and differential scanning calorimetry were performed to identify the physicochemical interaction between drug and carriers. Dispersible tablets and effervescent tablets were compared with tablet containing plane drug for dissolution profile. Dissolution of DT improved significantly in SD product (<95% in 1 min).

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Formulation and evaluation of dispersible taste masked tablet of roxithromycin

2008-12-20T12:44:00.001+05:30

oxithromycin is a broad spectrum, semisynthetic macrolide antibiotic, having bitter taste. In the present study, an attempt has been made to mask the bitter taste of roxithromycin by complexation technique. Weak cation exchange resins Indion 214 and Amberlite IRP64, polymer carbopol 934P were used in formulation of complexes with the drug. The loading process was optimized for the pH of loading solution and resin or polymer:drug ratio. The complexes were evaluated for bulk density, angle of repose, taste masking, and in vitro drug release. In vitro drug release studies showed more than 80% drug release from the optimized formulation within 30 min. Amberlite IRP64 was found to be better complexing agent for masking the bitter taste of roxithromycin.

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Simultaneous spectrophotometric estimation of rabeprazole sodium and itopride hydrochloride in capsule formulations

2008-12-20T12:42:00.001+05:30

A simple, precise, and economical procedure for the simultaneous estimation of rabeprazole sodium and itopride hydrochloride in tablet formulation has been developed. Rabeprazole sodium belongs to the class of proton pump inhibitor and Itopride hydrochloride belongs to the class of anticholinesterase activity as well as dopamine D2 receptor antagonistic activity, is being used for the symptomatic treatment of various gastrointestinal motility disorders. The present method involves the solving of simultaneous equations (Vierodt’s method). Rabeprazole sodium has absorbance maxima at 283 nm in phosphate buffer (pH 7.4) and itopride hydrochloride absorbance maxima at 258 nm in phosphate buffer (pH 7.4). Both these drugs obey Beer’s law in the concentration range employed for the present method. The result of analysis has been validated statistically by recovery studies. The slope and intercept for rabeprazole sodium were 0.0407 and 0.02 and for itopride hydrochloride were 0.0214 and 0.168, respectively, as determined by the method of least squares. The results were found satisfactory and reproducible. The method was applied successfully for the estimation of rabeprazole sodium and itopride hydrochloride simultaneously in tablet dosage to form without the interference of common excipients.

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Sustained release tablet of theophylline by hot melt wax coating technology

2008-12-20T12:38:00.001+05:30

Coating is one of the effective method used for sustaining the release of dosage form. There are various hydrophilic and hydrophilic polymers which are use to sustain the drug release. Waxes are one of the material which can be use to coat the drug in order to control the release. Coating with waxes can be achieved by dissolving it in suitable solvent or by hot melt wax coating. Hot melt coating technique defined as the application of fine layer of coating material in molten state over the substrate. Hot melt coating technique is widely used to coat granules, pellets and tablets in order to sustained the drug release, mask the bitter taste of drug, improve stability etc. Hot melt wax coatings have various advantages over wax solution coating. Toxicity of the organic solvent residues and the influence of environmental protection are major problems associated with solvent coating. The main goal of this study was to study the effect of different coating technique i.e. pan spray method and pan pour method on release pattern of theophylline and also to study the effect of different pore former like sodium laurel sulphate (SLS) and hydroxyl propyl methyl cellulose (HPMC) on release pattern. It was found that pan spray technique is the best technique to control the release due to uniform film formation, while pan pour method showed variation in release of drug from same batch this was due to non uniform coating of tablets and very low coating efficiency. If we compare the effect of pore former it was found that release of drug can be controlled by using suitable concentration of pore former while faster release was seen when SLS was used as a pore former in lower concentration than HPMC.

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Formulation, development and evaluation of patient friendly dosage forms of metformin, Part-III: Soluble effervescent tablets

2008-12-20T12:35:00.001+05:30

Metformin hydrochloride is an orally administered antihyperglycemic agent, used in the management of non-insulin-dependant (type-2) diabetes mellitus. Difficulty in swallowing (dysphagia) is common among all age groups, especially in elderly and pediatrics. Unfortunately, a high percentage of patients suffering from type-2 diabetes are elderly people showing dysphagia. The above problem becomes even more severe due to high dose (500-1000 mg) and need for daily intake of metformin. Thus, the above titled work was undertaken to provide patient friendly dosage form. Not only metformin is poorly compressible (Carr’s index 37), but effervescent ingredients are also poorly compressible so, method of wet granulation was used for preparation of tablets using absolute alcohol as binder. Metformin effervescent tablets were prepared using citric acid (CA), tartaric acid (TA), and treated sodium bicarbonate (heating at 120°C for 30 min), glycine, talc, sucralose, and mango flavor. Controlled heating of sodium bicarbonate formed a sheath or desiccant skin of sodium carbonate on bicarbonate nucleus leading to surface passivation which prevents onset effervescent reaction in presence of moisture leading to stability. Of all combinations, CA and TA in the molar ratio 1:2 was found to be most stable as higher amount of least hygroscopic TA protects hygroscopic CA from the attack of moisture. Also, it was found that using treated sodium bicarbonate in stoichiometric ratio gave substantially stable effervescent tablets on short term stability study (room temperature and humidity and 75% relative humidity (RH) and room temperature) as sodium carbonate preferentially absorbs moisture. All the ingredients selected were water soluble.

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Formulation, development and evaluation of patient friendly dosage forms of metformin, Part-II: Oral soft gel

2008-12-20T12:32:00.001+05:30

Dionvenience of administration and patient compliance are gaining significant importance in the design of dosage forms. Metformin hydrochloride is an orally administered antihyperglycemic agent, used in the management of non-insulin-dependant (type-2) diabetes mellitus. Difficulty in swallowing (dysphagia) is common among all age groups, especially in elderly and pediatrics. Unfortunately, a high percentage of patients suffering from type-2 diabetes are elderly people showing dysphagia. Persons suffering from dysphagia may get choked when they consume liquid formulation, thus to alleviate such problem liquid formulation of high viscosity was prepared. Formulation of oral soft gel batches of metformin was carried out using hydrophilic polymer gellan gum at concentrations ranging from 0.2-0.4% w/v and sodium citrate at two different concentrations (0.3% and 0.5%). The prepared batches were evaluated for appearance, viscosity, pH, drug content, syneresis, in vitro drug release, and taste masking. The batch with 0.4% w/v gellan gum and 0.5% sodium citrate not only showed 85% drug release at 15 min, but all the desired organoleptic properties. The taste masking was carried out using nonnutritive sugar and flavors. The optimized batch showed substantial stability when subjected to short term stability study (0-8°C and Room temperature). The problem of dose measurement by patients was outweighed as oral medicated gels are to be packed in unit dose container.

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Formulation, development and evaluation of patient friendly dosage forms of metformin, Part-I: Orally disintegrating tablets

2008-12-20T12:31:00.000+05:30

Metformin hydrochloride is an orally administered antihyperglycemic agent, used in the management of non-insulin-dependant (type-2) diabetes mellitus. Difficulty in swallowing (dysphagia) is common among all age groups, especially in elderly and pediatrics. Unfortunately, a high percentage of patients suffering from type-2 diabetes are elderly people showing dysphagia. In this study, orally disintegrating tablets were prepared using direct compression and wet granulation method. First, the tablets of metformin were prepared using starch RX1500 and microcrystalline cellulose by direct compression. The tablets showed erosion behavior rather than disintegration. Then lactose was incorporated which created pores to cause burst release of drug. But these tablets did not give good mouth feel. Thus, Pearlitol SD 200 (spray dried mannitol) was used to prepare tablets by wet granulation (10% polyvinylpyrrolidone in Isopropyl alcohol as binder). The optimized batches of tablets (LMCT3 and MP13) not only exhibited desired mouth feel but also disintegration time, in vitro dispersion time, water absorption ratio, and in vitro drug release. All the batches contained 15% starch 1500 and 4% of croscarmellose sodium. The optimized batches prepared by direct compression and wet granulation showed 85% drug release at 4 min and 8 min, respectively. The strong saline and slight bitter taste of the drug was masked using nonnutritive sweetener and flavor.

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A New Approach: Enhancement of solubility of Rofecoxib

2008-12-20T12:24:00.000+05:30

The present study is aimed at improving the dissolution of poorly soluble drug, rofecoxib. Rofecoxib, being a drug, basic in nature shows a better solubility in acidic environment. Hence, an attempt was made to provide an acidic microenvironment around the drug molecules by incorporating various freely soluble acidic substances. Addition of such additives provides a dual effect of not only providing an acidic microenvironment but also imparts solubilizing effects due to the free water-soluble nature of the additives used. In the present work, β-cyclodextrin (β-CD) complexes of rofecoxib were prepared and solubilizing additives such as citric acid and ascorbic acid were incorporated in various proportions. Dissolution studies were performed in both HCl buffer (pH 1.2) and phosphate buffer (pH 7.4). The results have shown an enhanced dissolution rate of rofecoxib in both media from beta-cyclodextrin. complex, and a further enhancement of dissolution was found in presence of ascorbic acid as well as citric acid. Differential scanning calorimetery (DSC) and infrared spectroscopy (IR) spectral studies performed on the solid complexes have shown that there is no interaction of the drug with β-CD and the additives. Hence, β-CD enhances the solubility of rofecoxib, and by creating an acidic microenvironment around the drug molecules, solubility of rofecoxib can be enhanced further, which in turn will enhance the absorption of rofecoxib and produce a better pharmacological activity.

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Development of Mouth Dissolving Tablets of Clozapine Using Two Different Techniques

2008-12-20T12:17:00.001+05:30

Mouth dissolving tablets constitute an innovative dosage form that overcomes the problems of swallowing and provides a quick onset of action. In view of enhancing bioavailability an attempt has been made to study two different methods direct compression and sublimation in formulation of mouth dissolving tablets of clozapine. Total four formulations using various superdisintegrants and subliming agents were prepared. All prepared formulations were evaluated for physico-chemical parameters. The formulations exhibited good disintegration properties with total disintegration time in the range of 25 to 35 s. Comparative evaluation of two methods showed direct compression method is a better alternative to sublimation method as its formulations rapidly disintegrate in oral cavity. In vitro cumulative percentage drug release for formulations prepared by direct compression with explotab superdisintegrants shows 99.79 while sublimation method using camphor 93.58 release in 12 min. Kinetic studies indicated that all the formulations followed fi rst order release with diffusion mechanism.

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A Study on Improvement of Solubility of Rofecoxib and its effect on Permeation of Drug from Topical Formulations

2008-12-20T12:16:00.001+05:30

Rofecoxib, a practically insoluble cox-2 selective nonsteroidal antiinfl ammatory agent was subjected to improvement in solubility by preparing its binary mixtures with β cyclodextrin using various methods such as physical mixing, co-grinding, kneading with aqueous methanol and co-evaporation from methanol-water mixture. Characterization of the resulting binary mixtures by differential scanning calorimetry and X-ray diffraction studies indicated partial amorphization of the drug in its binary mixtures. In vitro dissolution studies exhibited remarkable increase in rate and extent of dissolution of the drug from its complexes with β-cyclodextrin. Pure rofecoxib as well as its co-ground binary mixture were formulated as aqueous gels for topical application. In vitro skin permeation of rofecoxib from formulation containing rofecoxib-cyclodextrin complex was signifi cantly higher (p<0.05)>hr as compared to formulation containing pure rofecoxib. This could be attributed to better solubility of binary mixture in the aqueous gel vehicle leading to greater concentration gradient between the vehicle and skin and hence higher flux of the drug.

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Herbal Excipients in Novel Drug Delivery Systems

2008-12-20T12:13:00.001+05:30

The use of natural excipients to deliver the bioactive agents has been hampered by the synthetic materials. However advantages offered by these natural excipients are their being non-toxic, less expensive and freely available. The performance of the excipients partly determines the quality of the medicines. The traditional concept of the excipients as any component other than the active substance has undergone a substantial evolution from an inert and cheap vehicle to an essential constituent of the formulation. Excipients are any component other than the active substance(s) intentionally added to formulation of a dosage form. This article gives an overview of herbal excipients which are used in conventional dosage forms as well as novel drug delivery systems.

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Pharmacokinetics: Regulatory, Industrial, Academic Perspectives (Drugs and the Pharmaceutical Sciences)

2008-12-20T09:17:00.002+05:30

Offering a unique, multidisciplinary approach, this state-of-the-art Second Edition details the rapidly changing role that clinical and non-clinical pharmacokinetics and drug metabolism play in the discovery and development of drug therapies -- emphasizing often overlooked regulatory, scientific, and economic issues.

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Drug Development Process: Increasing Efficiency & Cost Effectiveness (Drugs and the Pharmaceutical Sciences)

2008-12-20T09:14:00.001+05:30

Publisher: Informa HealthCare
Number Of Pages: 447
Publication Date: 1996-08-15
ISBN-10 / ASIN: 0824797272
ISBN-13 / EAN: 9780824797270
Binding: Hardcover

Product Description:

Containing contributions from the many disciplines involved in a drug's evolution, this timely volume examines the entire pharmaceutical development process, emphasizing approaches to increasing efficiency and reducing costs.

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Pharmaceutical Preformulation

2008-12-20T09:11:00.004+05:30

This book addresses problems and solutions of formulation and preformulation with which I have concerned myself for 34 years. When I was employed in the pharmaceutical industry I worked at functions, in the 1960's, which were the precursors of preformulation, and my early publications dealt with such matters. In the following decades advances have been made in methodology and the realm of preformulation has grown. Theory and the way in which problems are viewed have also undergone change. The text deals with the pharmaceutical aspects of preformulation, not the synthetic nor the analytical aspects. It takes its vantage point at the point in time when the pharmaceutical preformulator first obtains a sample of the drug substance, and it explores the physical, chemical and technological aspects that are needed for a full exploration of the potential advantages and disadvantages of the drug substance. It is only through the understanding of underlying principles that adequate exploration can be carried out.

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Pharmaceutical Process Engineering (Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs)

2008-12-19T10:10:00.002+05:30

Book Description

Summarizing fundamental engineering principles and operations critical to converting bulk pharmaceutical products into patient-ready and appropriate drug delivery dosage forms, Pharmaceutical Process Engineering facilitates comprehensive understanding of the practical aspects of drug production in an accessible, step-by-step format. It provides a pharmaceutical perspective on unit operations that improves communication among diverse professionals in the field-from pharmaceutical researchers to chemical and industrial engineers-and fully covers the relationship of pharmaceutical development to the application of key concepts and major unit operations in pharmaceutical engineering.

Features:

* the application of key concepts and major unit operations in pharmaceutical engineering
* principles of heat transfer, mass transfer, and fluid flow
* control of global and local manufacturing environments
* the preparation of sterile materials such as water for injection
* drying, evaporation, and crystallization processes for concentrated drug solutions and solids
* techniques of filtration and centrifugation for collecting or removing drug particles
* particle size reduction, mixing, granulation, and drying methods for capsule and tablet
* the manufacture of biological materials
* and more!

Pharmaceutical Process Engineering makes a noteworthy reference for industrial, research, and clinical pharmaceutical scientists; chemical and industrial engineers; biologists and toxicologists; biostatisticians; analytical chemists; and quality control, quality assurance, and regulatory compliance managers; and serves as an essential text for upper-level undergraduate and graduate students in these disciplines.

Contents

1. Fundamentals
* Fluid Flow
* Heat Transfer
* Mass Transfer
* Powders

2. Processes
* Air Conditioning and Humidification
* Drying
* Solid-Liquid Extraction
* Crystallization
* Evaporation and Distillation
* Filtration
* Size Reduction and Classification
* Mixing
* Solid Dosage Forms
* Sterilization
* Bioprocessing

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Introduction to the Pharmaceutical Regulatory Process (Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs)

2008-12-19T09:13:00.002+05:30

Providing in-depth coverage of the procedures utilized by pharmaceutical companies for regulatory compliance, this reference describes the history and development of regulations, standards, and guidelines that affect pharmaceutical product approval and commercial sale in the United States-standing alone as the only authoritative guide to address the complex web of regulatory requirements, application processes, and quality control issues influencing the pharmaceutical industry.

Providing in-depth coverage of the procedures utilized by pharmaceutical companies for regulatory compliance, this reference describes the history and development of regulations, standards, and guidelines that affect pharmaceutical product approval and commercial sale in the United States-standing alone as the only authoritative guide to address the complex web of regulatory requirements, application processes, and quality control issues influencing the pharmaceutical industry.

Demonstrates how the FDA monitors and ensures pharmaceutical product safety and efficacy.

Offering critical information in every chapter, this guide

* Clarifies requirements for the preparation of product submissions in compliance with regulatory standards
* Details current efforts to streamline the regulatory process-including a specific example applicable to antibiotic products
* Covers the processes and issues related to the approval process for registration of prescription, generic, and over-the-counter drugs
* Considers patent issues, as well as the registration of pharmaceutical products
* Contains clinical research requirements for new drug applications
* Anticipates changes that may be required in the manufacturing process after the product application is approved
* Compares regulations for biological and pharmaceutical chemical products

Introduction to the Pharmaceutical Regulatory Process is must-have reading for all pharmaceutical engineers; pharmaceutical quality control and reliability managers; regulatory affairs professionals and attorneys; federal, state, and local officials responsible for compliance; and upper-level undergraduate and graduate students in these disciplines.

Contents

1. Legal
1. A HPharmaceutical Regulation Before and After the Food, Drug, and Cosmetic Act
2. New Drug Approval Process: Before and After 1962
3. FDA Regulation of Biological Products
4. Generic Drug Approval Process: Pre-1984 History Concerning Generic Drugs
5. Generic Drug Approval Process: Post 1984: Waxman-Hatch Reform
6. Food and Drug Administration Modernization Act
7. FDA's Antibiotic Regulatory Scheme: Then and Now
8. Pioneer and Generic Drugs: Balance Between Product Life Cycle
9. The Influence of the Prescription Drug User
Fee Act on the Approval Process
10. Clinical Research Requirements for New Drug Applications

2. FDA Requirements for Product Approvals and After
11. Active Pharmaceutical Ingredients
12. Obtaining Approval of a New Drug
13. Obtaining Approval of a Generic Drug
14. Current Good Manufacturing Practice and the Drug Approval Process
15. CMC Post-Approval Regulatory Affairs: Constantly Managing Change
16. The Influence of the USP on the Drug Approval Process
17. Ways and Means to U.S. Registration of Foreign Drugs
18. Common Technical Document-Quality (M4-Q): One Regulatory Participant's Perspective
19. 21 CFR Part 11: Compliance and Beyond
20. Marketing and Advertising Promotion: The Impact of Government Regulations
21. Approval and Marketing of Nonprescription or OTC Human Drugs

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FDA Announces Class I Recalls Of Two Unapproved Devices

2008-12-19T09:08:00.000+05:30

December 16, 2008

The U.S. Food and Drug Administration (FDA) announced a Class 1 recall recently for two unapproved and uncleared devices whose manufacturers claimed could treat various medical conditions. A Class 1 recall means that there is a reasonable probability that the use of a device will cause adverse health consequences or death.

The manufacturers, VIBE Technologies of Greeley, Colo., and Nebion LLC of Los Angeles, Calif., claimed their devices treated conditions ranging from cancer to migraines. The FDA is concerned that based upon the original health claims made by the company, patients may forgo approved therapies, and that this could result in more severe illness or death.

"These recalls underscore the importance of taking action against manufacturers who make false medical claims for their devices," said Daniel G. Schultz, M.D., director of the FDA's Center for Devices and Radiological Health. "One of the FDA's primary responsibilities is protecting consumers from harm that can be caused by manufacturers who try to sidestep the approval and clearance process."

Vibrational Integrated Bio-photonic Energizer device
On April 11, 2008, the FDA issued a warning letter to VIBE Technologies stating that the agency's November 2007 inspection of the facility showed that the company had not obtained FDA marketing approval or clearance for the Vibrational Integrated Bio-photonic Energizer (VIBE device), which claims to treat cancer, infections, and depression. The FDA also cited the company for substantial deviations from the current Good Manufacturing Practice/Quality System regulation.

VIBE Technologies initiated a recall of 840 VIBE devices in an April 3, 2008, letter sent to users. VIBE Technologies agreed to stop promoting and marketing the VIBE device, and will contact all those who had purchased it to ensure no other unsubstantiated medical claims are being made. The FDA has requested that the company update its recall notices to state that the VIBE device is not intended for the treatment of any diseases or medical conditions.

The FDA is aware of information that suggests that the VIBE device has been used in cancer patients. There is one death that occurred in a patient who used this device. However, FDA has not verified that there is any association between the death and the VIBE device.

HLX8 device
In June 2008 FDA inspected Nebion, LLC, which revealed that the company had not obtained FDA marketing approval or clearance for the HLX8 device, which claims to treat cancer, migraines, arthritis, and ruptured discs. The inspection also uncovered substantial deviations from the Current Good Manufacturing Practice/Quality System regulation.

Nebion recalled eight HLX8 devices on July 2, 2008, and notified their customers to stop using the devices immediately and to contact Nebion for their retrieval.

Nebion's first recall letter did not address the potential risks associated with the HLX8 device, but the company has recently notified FDA that they will issue a second letter that identifies potential health hazards. The FDA has not received any reports of injuries or deaths linked with the HLX8 device.

Under federal law, products that claim to diagnose a disease or condition, cure, mitigate, treat or prevent disease, or that are intended to affect the structure or function of the body are devices subject to FDA jurisdiction and may require FDA approval or clearance prior to marketing. Premarket approval is the most stringent type of FDA device review and is for devices with a high level of risk, such as those that support or sustain human life. FDA clearance is for lower risk devices that are shown to be as safe and effective as a similar device already on the market.

Neither VIBE Technologies nor Nebion has demonstrated to the FDA that their device is safe and effective at curing or treating diseases as claimed.

Bi-layer tablets - why special technology is required

2008-12-19T09:01:00.000+05:30

Several pharmaceutical companies are currently developing bi-layer tablets. For a variety of reasons: patent extension, therapeutic, marketing to name a few. To reduce capital investment, quite often existing but modified tablet presses are used to develop and produce such tablets. This article explains why the development and production ofquality bi-layer tablets needs to be carried out on purpose-built tablet presses to overcome common bi-layer problems, such as layer-separation, insufficient hardness, inaccurate individual layer weight control, cross-contamination between the layers, reduced yield, etc. Using a modified tablet press may therefore not be your best approach to producing a quality bi-layer tablet under GMP-conditions. Especially when in addition high production output is required.

Bi-layer tablets: quality and GMP-requirements
To produce a quality bi-layer tablet, in a validated and GMP-way, it is important that the selected press is capable of:

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Herbal Drugs: Ethnomedicine to Modern Medicine

2008-12-18T09:11:00.002+05:30

This reference work covers for the first time the herbal drugs used in ethnomedicine and validated on modern scientific basis. In depth information prepared by experts traces the evolution of herbal drugs with civilization and their use as antioxidants, anticancerous, chemopreventors, memory enhancers, neuroprotective, immunomodulator, anti-inflammatory, and in stroke, cardiovascular disorders, erectile dysfunction; also covering safety issues and toxic effects. Many of our modern medicine have come from traditional use of plants such as Curcuma, Ginkgo, and Ginseng. Therefore, information on herbal drugs, from ethnomedicine to modern use, has been arranged based on their involvement in various ailments. This book offers researchers working on diverse aspects of medicinal plants a complete coverage of botany, ethnology, pharmacology, toxicology and medicinal properties of medicinal plants. It provides essential source material to all working in the fields of agriculture, botany, pharmacy, traditional systems of medicine and drug industry.

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Tablet and Capsule Manufacturing

2008-12-18T09:08:00.001+05:30

The Manufacturing Process was created for companies and individuals to gain a complete understanding of the basic requirements needed to make tablets and capsules.

The objective is that the reader will gain a quick, yet comprehensive understanding of solid dosage operations used in the manufacturing process.

The focus will be a step by step explanation of each unit dose operation, common equipment, and practical knowledge of each operation.

The main topics are Formulation, Blending, Milling, Granulation, Drying, Final Blending, Tableting, Tablet Press Tooling, Coating, and Encapsulation.

Common tablet & capsule defects and problem solving are also part of the objective......

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A Tablet Making Training Resource for Tablet Making Professionals

2008-12-18T09:05:00.000+05:30

Improving manufacturing skills within a company is critical to the success and key to continuous
quality improvement.

Tablet Pro is exactly what our industry is about today; The methodology, documentation and mindset required to meet the needs of our changing industry.

This means that everyone connected to the manufacturing environment must comprehend the basics of Tablet Making. Managers and Supervisors must now understand the fundamentals of making tablets, because if they do not know the basics they cannot properly support the.....

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Shifting high-speed powder induction into overdrive

2008-12-18T09:02:00.000+05:30

Every process engineer who has worked with powders such as fumed silica, CMC, guar, xanthan, carageenan, alginates and other thickeners has come face to face with one of the toughest challenges in mixing. Many of the powders that are most often used inthe process industries are hard to wet out and mix.They will float for hours on the surface of a liquid batch. Even with vigorous agitation, they’ll sail in circles on the slopes of a vortex and resist being drawn down into the batch. Once submerged, they form agglomerates that continue to resist being separated and dispersed.

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High-Throughput Analysis in the Pharmaceutical Industry

2008-12-17T12:18:00.003+05:30

High throughput analysis plays a critical role in the pharmaceutical industry. The ever-shortening timelines and high costs of drug discovery and development have brought about the need for high throughput approaches to methods that are currently used in the industry. Written and edited by well-known contributors who remain active in this line of research, this book systematically describes high throughput analysis for the pharmaceutical industry, including advanced instrumentation and automated sample preparation. The text discusses various techniques, including HPLC, MALDI-MS, and LC-MS/MS methods, with an emphasis on the later stage of drug development, including pharmacokinetics.

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Handbook of Basic Tables for Chemical Analysis

2008-12-17T12:13:00.002+05:30

If you are a researcher in organic chemistry, chemical engineering, pharmaceutical science, forensics, or environmental science, you make routine use of chemical analysis. And like its best-selling predecessor was, the Handbook of Basic Tables for Chemical Analysis, Second Edition is your one-stop source for the information needed to design chemical analyses. Here's what is new in the Second Edition:"New chapters on solutions, electroanalytical methods, electrophoresis, and laboratory safety"An expanded section on gas chromatography that includes data on compounds that attack common detectors"New information on detector optimization"An updated section on high performance liquid chromatography that provides the most recent chiral stationary phases, detector information, and revised solvent tables"Updated information on the most useful "wet" chemistry methods"Enlarged section of Miscellaneous Tables Going far beyond the landmark first edition in terms of scope and applications, the second edition provides current and updated data culled from a wide range of resources and consolidated into a concise yet easy-to-use format. The book's laser-like focus on core information gives you the knowledge you need when you need it - at the decision point.

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Validation of Clean-in-place System on a Capsule Filling Machine

2008-12-17T12:04:00.001+05:30

The aim of this study was to validate the automated clean-in-place (CIP) system installed on a capsule filling machine to determine its ability to adequately eliminat contaminants. The results obtained from the proposed cleaning validation trial showed that all the soluble tracer was removed after the washing procedure. At the end of CIP procedure the discharged water had the same pH, phosphate content and total organic content as the supplied water. Lack of cross-contamination in the product was also demonstrated and a recovery trial highlighted the complete elimination of the tracer from the machine.

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Remington: The Science and Practice of Pharmacy

2008-12-16T14:36:00.003+05:30

For over 100 years, Remington has been the definitive textbook and reference on the science and practice of pharmacy. This Twenty-First Edition keeps pace with recent changes in the pharmacy curriculum and professional pharmacy practice. More than 95 new contributors and 5 new section editors provide fresh perspectives on the field. New chapters include pharmacogenomics, application of ethical principles to practice dilemmas, technology and automation, professional communication, medication errors, re-engineering pharmacy practice, management of special risk medicines, specialization in pharmacy practice, disease state management, emergency patient care, and wound care. Purchasers of this textbook are entitled to a new, fully indexed Bonus CD-ROM, affording instant access to the full content of Remington in a convenient and portable format.

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SAS Programming in the Pharmaceutical Industry

2008-12-16T14:28:00.002+05:30

At last! A real-world reference guide for clinical trial SAS programming, packed with solutions that programmers can apply to their day-to-day problems. Discover key techniques and tools available within Base SAS (including the macro language and PROC SQL), SAS/GRAPH, and SAS/STAT that can be used to resolve many common issues in working with clinical trial data. Organized to reflect the statistical programmer's work flow, this user-friendly text begins with an introduction to the working environment, then presents chapters on importing and massaging data into analysis data sets, producing clinical trial output, and exporting data. Valuable plug-and-play programming examples are provided throughout. Whether you're a novice seeking an introduction to SAS programming for the pharmaceutical industry or a junior-level programmer exploring new approaches to problem solving, you'll find a wealth of practical suggestions to help you sharpen your skills.

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USP30-NF25 (2007)

2008-12-16T12:16:00.001+05:30

The United States Pharmacopeia is a compendium of quality control tests for drugs and excipients to be introduced into a medicinal formulation. It is published every year [1] by the United States Pharmacopoeial Convention. It forms the basis of enforcement actions by the U.S. Food and Drug Administration and the U.S. Drug Enforcement Administration and is the official pharmacopoeia of the U.S.A. and many other nations. Therefore, in case of a dispute, those methods for, amongst others, identification, assay and purity determination of a drug substance or excipient which are stated in the USP will be the legally binding ones.

Within the field the compendium is referred to simply as the USP. The initials USP are affixed to materials' names to indicate that they conform to the specifications in the USP and may be used medicinally.

Who Needs USP–NF

USP–NF is essential in the following types of industries:

* Pharmaceuticals — prescription and nonprescription drugs
* Biological and biotechnology products
* Blood and blood products
* Cosmetics
* Dietary supplements
* Excipients/other drug ingredients
* Medical devices
* Medical gases
* Veterinary drugs

In each of these industries, USP–NF is an essential resource for scientists, managers, supervisors, and directors in:

* Quality control
* Quality assurance
* Regulatory/compendial affairs
* Research and development
* Method development/analytical services
* Corporate management

USP–NF also is an important reference for pharmacies, libraries, universities, and schools of medicine and pharmacy.
How USP–NF Helps

Only the USP–NF provides the official standards enforceable by the U.S. Food and Drug Administration for drugs and related products manufactured and marketed in the United States. In addition, it serves as a clear, step-by-step guide for the specifications—tests, procedures, and acceptance criteria—required for pharmaceutical manufacturing and quality control.

USP–NF helps to:

* Ensure compliance with official standards
* Work to world-recognized standards of precision and accuracy
* Validate test results against proven benchmarks
* Establish and validate in-house standard operating procedures, procedures, and specifications
* Expedite new product development and approvals

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USP27-NF22

2008-12-16T12:02:00.004+05:30

The U.S. Pharmacopeia and the National Formulary are the official, legally recognized compendia of standards of strength, quality, purity, packaging, labeling, and storage for drugs and excipients. USP/NF also provides standards for devices, diagnostics, botanicals, and vitamins and minerals.
The USP/NF CD provides the same legally recognized information as the print version, integrates supplements into the publication and includes comprehensive tools for rapidly searching more than 2,500 pages of information.

The new USP--NF for 2004 includes substantial enhancements and revisions:
More than 70 new monographs
More than 340 revised monographs
6 brand-new general chapters
Good Compounding Practices
Monitoring Devices -- Time, Temperature, and Humidity
Pharmaceutical Calculations in Prescription Compounding
Pharmaceutical Compounding -- Sterile Preparations
Pharmacopeial Harmonization
Crystallinity Determination by Solution Calorimetry
20 revised general chapters
Helpful new guidelines to track related tests and procedures in general chapters
A separate section on Dietary Supplements with more than 200 monographs for vitamin-mineral combination products as well as for botanicals and non-botanicals used in nearly 900 dietary supplement products.
A new and improved table of contents.
Other important changes are in the pipeline. Supplements included in your subscription will bring you further vital updates!

Download Links:

http://mihd.net/a7wqbd
http://mihd.net/789ans
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passward: ipopfqq2005_us

European Pharmacopoeia:

2008-12-16T11:51:00.001+05:30

European Pharmacopoeia: 2001 Supplement

Use SERIAL IN CAPITAL LETTERS:
01U2001E-5XNS2BL2N4

Download Links:

http://rapidshare.com/files/10581730/EUROPEAN_PHARMACOPEA.part1.rar
http://rapidshare.com/files/10597604/EUROPEAN_PHARMACOPEA.part2.rar
http://rapidshare.com/files/11157437/EUROPEAN_PHARMACOPEA.part3.rar
http://rapidshare.com/files/10605346/EUROPEAN_PHARMACOPEA.part4.rar

Simultaneous Determination of Valsartan and Hydrochlorothiazide in Tablets by RP-HPLC

2008-12-16T11:04:00.002+05:30

A simple, reproducible and efficient reverse phase high performance liquid chromatographic method was developed for simultaneous determination of valsartan and hydrochlorothiazide in tablets. A column having 200 × 4.6 mm i.d. in isocratic mode with mobile phase containing methanol: acetonitrile: water: isopropylalcohol (22:18:68:2; adjusted to pH 8.0 using triethylamine; v/v) was used. The flow rate was 1.0 ml/min and effluent was monitored at 270 nm. The retention time (min) and linearity range (µg/ml) for valsartan and hydrochlorothiazide were (3.42, 8.43) and (5-150, 78-234), respectively. The developed method was found to be accurate, precise and selective for simultaneous determination of valsartan and hydrochlorothiazide in tablets.

Valsartan, (S)-N-(1-Oxopentyl)-N-[[2í-(1H-tetrazol-5- yl)[1,1í-biphenyl]-4-yl]methyl]-L-valine, is an orally active specific angiotensin II receptor blocker effective in lowering blood pressure in hypertensive patients¹. A number of high performance liquid chromatographic (HPLC) methods are available for separation and quantification of valsartan from pharmaceutical dosage forms². Hydrochlorothiazide is a diuretic of the class of benzothiadiazines widely used in antihypertensive pharmaceutical formulations, alone or in combination with other drugs, which decreases active sodium reabsorption and reduces peripheral vascular resistance³. It is chemically 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide, and was successfully used as one content in association with other drugs^4-9in the treatment of hypertension. Simultaneous determination of both drugs is highly desirable as this would allow more efficient generation of clinical data and could be more cost-effective than separate assays. There are very few methods appearing in the literature for the simultaneous determination of valsartan and hydrochlorothiazide in tablets. Since these methods were based on HPLC and UV-derivative spectrophotometry^10-11, the procedure was inconvenient for determination and the run times were rather long. The aim of this study was to develop a simple, precise and accurate reverse-base high performance liquid chromatographic method to estimate valsartan and hydrochlorothiazide in tablets. This method was simple and rapid and provides accurate and precise results, as compared with other methods which have been reported. Criteria employed for assessing the suitability of said solvent system were cost-effectiveness in terms of time required for analysis, solvent noise and preparatory steps involved in the extraction of the drug from the formulation excipients for the estimation of drug contents. The retention times for valsartan and hydrochlorothiazide were 3.42 and 8.43 min, respectively. The typical chromatograms of the drugs are shown in fig. 1. The peak shapes of both drugs were symmetrical and asymmetry factor was less than 1.3.

Pharmaceutical grade valsartan and hydrochlorothiazide were supplied by National Institute for the Control of Pharmaceutical and Biological Products and were used without further purification. All chemicals and reagents were of HPLC grade and were purchased from Jiangsu Hanbon Sci. & Tech. Co. Ltd.

HPLC system consisted of a pump (model LC-10AT plus). Manual injector was used. Loop used was of 20-µl capacity per injection. UV detector (model SPD-10AV plus) was used. Detection was carried out at 270 nm and the software used was Anstar Chromatographic Data System. Diamonsil (TM) C18 (200 × 4.6 mm, 5 µm) column was used. Different mobile phases were tested in order to find the best conditions for composition of mobile phase was determined to be methanol- acetonitrile- water-isopropylalcohol (22:18:68:2; v/v), and adjusted pH value to 8 with triethylamine. Flow rate was set to 1.0 ml/min.

Standard stock solution containing 0.01 and 0.00157mg/ml of valsartan and hydrochlorothiazide,

Fig. 1: HPLC Chromatogram of valsartan and hydrochlorothiazide in tablets.

respectively was prepared by dissolving 10 and 1.57 mg of both drugs in 1000 ml of mobile phase. For estimation of valsartan and hydrochlorothiazide in tablets, an accurately weighed quantity of tablet powder equivalent to 10 mg valsartan and 1.57 mg hydrochlorothiazide were transferred to a 1000 ml volumetric flask, diluted with mobile phase, sonicated for 10 min and further diluted to 1000 ml with mobile phase. The solution was sonicated before it was used to analysis.

The plot of peak area of standard solutions versus concentration was found to be linear in the range of 5-150 μg /ml and 78-234 μg /ml for valsartan and hydrochlorothiazide respectively and coefficient of correlation (r²) was 0.9997 and 0.9998, respectively.

Amounts of drug powder equivalent to 100% of label claim, respectively of valsartan and hydrochlorothiazide were accurately weighed and assayed. The system repeatability was determined by six repeated applications. Repeatability of sample application and measurement of peak area were expressed in terms of relative standard deviation. Method repeatability was obtained from relative standard deviation by repeating six times during the same day for intraday precision. Intermediate precision was also done.

The reversed-phase HPLC method was developed to provide a specific procedure suitable for the rapid quality control analysis of valsartan and hydrochlorothiazide as referee method for the developed derivative method. To evalutate HPLC method robustness, a few parameters were deliberately varied; the parameters included pH of buffer and differents percentages of methanol and acetonitrile in mobile phase. Specificity of the methods was determined by the complete separation of valsartan and hydrochlorothiazide with other parameters like retention time, asymmetry and capacity factor. The condition of the method was exactly effective and efficient.

TABLE 1: SYSTEM SUITABILITY PARAMETERS

Parameters	Valsartan	Hydrochlorothiazide
Retention time (min)	3.42	8.43
Asymmetry	1.204	1.045
Theoretical plate	4238	5616
Resolution factor	-	9.0
Calibration range (μg /ml)	5-150	78-234
Correlation coefficient (r²)	0.9997	0.9998

To study accuracy, reproducibility and precision of the proposed method, recovery experiments were carried out. The average percentage recovery of valsartan and hydrochlorothiazide was 99.2% and 98.8% respectively. The sample recovery in the formulation was in good agreement with what was claimed on the label. System suitability parameters are given in Table 1. Assay in the tablet dosage form was found to be 98.6% of valsartan and 97.8% of hydrochlorothiazide. The method was simple and the run time given was 15 min. The proposed method gives a good resolution between valsartan and hydrochlorothiazide within a short analysis time (<15>adopted for routine quality control analysis.

To summarize, the method was evaluated in a mass of facets, such as best condition, linear relation including coefficient of correlation, robustness, accuracy, reproducibility and precision. All the parameters above showed that this method, which was fairly efficient and convenient, can be used to determine of Valsartan and Hydrochlorothiazide in tablets simultaneously.

References

1. Markham A, Goa KL. Valsartan. A review of its pharmaco-logy and therapeutic use in essential hypertension. Drugs 1997;54:299-311.

2. Daneshtalab N, Lewanczuk RZ, Jamali F. High-performance liquid chromatographic analysis of angiotensin II receptor antagonist valsartan using a liquid extraction method. J Chromatogr B 2002; 766:345-9.

3. Carlucci G, Palumbo G, Mazzeo P, Quaglia MG. Simultaneous determination of losartan and hydrochlorothiazide in tablets by high-performance liquid chromatography. J Pharm Biomed Anal 2000; 23:185-9.

4. Schoenberger JA. Losartan with hydrochlorothiazide in the treatment of hypertension. J Hypertens 1995;13:S43-7.

5. Ramsay LE, Yeo WW. Double-blind comparison of losartan, lisinopril and hydrochlorothiazide in hypertensive patients with a previous angiotensin converting enzyme inhibitor-associated cough. J Hypertens 1995;13:(Suppl 1) S73-6.

6. McCrea JB, Lo MW, Tomasko L, Lin CC, Hsieh JY, Capra NL, et al. Absence of a pharmacokinetic interaction between losartan and hydrochlorothiazide. J Clin Pharmacol 1995;35:1200-6.

7. Ruilope LM, Simpson RL, Toh J, Arcuri KE, Goldberg AI, Sweet CS. Controlled trial of losartan given concomitantly with different doses of hydrochlorothiazide in hypertensive patients. Blood Press 1996;5:32-40.

8. Conlin PR, Elkins M, Liss C, Vrecenak AJ, Barr E, Edelman JM. A study of losartan alone or with hydrochlorothiazide vs nifedipine GITS In eldely patients with diastolic hypertension. J Hum Hypertens 1998;12:693-700.

9. Del Castillo D, Campistol JM, Guirado L, Capdevilla L, Martinez JG, Pereira P, et al. Efficacy and safety of losartan in the treatment of hypertension in renal transplant patients. Kidney Int Suppl 1998;68:S135-9.

10. Hillaert S, Van den Bossche W. Simultaneous determination of hydrochlorothiazide and severl angiotensin-II-receptor antagonists by capillary electrophoresis. J Pharm Biomed Anal 2003;31:329-39.

11. Satana E, Altinay S, Goger NG, Ozkan SA, Senturk Z. Simultaneous determination of valsartan and hydrochlorothiazide in tablets by first- derivative ultraviolet spectrophotometry and LC. J Pharm Biomed Anal

2001;25:1009-13.

Simultaneous HPTLC Determination of Rabeprazole and Itopride Hydrochloride from Their Combined Dosage

2008-12-16T10:59:00.000+05:30

A simple, precise, sensitive, rapid and reproducible HPTLC method for the simultaneous estimation of the rabeprazole and itopride hydrochloride in tablets was developed and validated. This method involves separation of the components by TLC on precoated silica gel G60F254 plate with solvent system of n-butanol, toluene and ammonia (8.5:0.5:1 v/v/v) and detection was carried out densitometrically using a UV detector at 288 nm in absorbance mode. This system was found to give compact spots for rabeprazole (Rf value of 0.23 0.02) and for itopride hydrochloride (Rf value of 0.75±0.02). Linearity was found to be in the range of 40-200 ng/spot and 300-1500 ng/spot for rabeprazole and itopride hydrochloride. The limit of detection and limit of quantification for rabeprazole were 10 and 20 ng/ spot and for itopride hydrochloride were 50 and 100 ng/spot, respectively. The method was found to be beneficial for the routine analysis of combined dosage form.

Rabeprazole and itopride hydrochloride¹ are available in combined capsule dosage form for the management of gastro esophageal reflux disease (GERD). Literature survey reveals that various analytical methods^2-9have been reported for rabeprazole and itopride hydrochloride in single dosage forms. The present paper aims to report a simple HPTLC method for estimation of rabeprazole and itopride hydrochloride in their combined dosage form.

Rabium-plus containing 20 mg/tab of rabeprazole and 150 mg/tab of itopride hydrochloride, which are manufactured and marketed by Intas Ltd. was estimated. Reference standard of rabeprazole and itopride hydrochloride were kindly supplied as a gift sample by Grandix Pharmaceuticals, Chennai and Abbott Laboratories, Goa. All chemicals and reagents used were of analytical grade and were purchased from SD Fine Chemicals, Mumbai. A Camag HPTLC system comprising of Camag Linomat V semi automatic sample applicator, Hamilton Syringe, Camag Twin trough chamber, Camag TLC Scanner-3, Camag WinCATS Software and stationary phase precoated silica gel G60F₂₅₄ were used.

The TLC plates were pre-washed with methanol and activated by keeping at 115° for about 30 min. The samples were spotted in the form of bands of width 6mm with Hamilton microlitre syringe on the precoated silica gel G₆₀F₂₅₄ plate (10×10 cm), slit dimension was kept at 5×0.45 mm, respectively. The mobile phase used was n-butanol:toluene:ammonia (8.5:0.5:1 v/v/v), chamber and plate saturation time of 30 min, migration distance allowed was 85 mm, linear ascending development was carried out in 10×10 cm, twin trough glass chamber. Subsequent to the development TLC plates were dried in a current of air. Densitometric scanning was performed at 288nm. The source of radiation utilized was deuterium lamp emitting a continuous UV spectrum.

Standard stock solution mixture of rabeprazole and itopride hydrochloride were prepared in methanol of 200 µg/ml and 1500 µg/ml. Aliquots of standard solution having concentration ranging from 40-200 ng/ spot and 300-1500 ng/spot (0.2, 0.4, 0.6, 0.8 and 1.0 µ1) of rabeprazole and itopride hydrochloride were applied on the TLC plate. The TLC plate was dried, developed and analysed as described earlier.

Twenty tablets of two different batches were chosen, weighed, powdered, transferred into a volumetric flask and extracted with methanol. The extract was filtered through Whatmann filter paper No 41 and residue was washed with methanol. Aliquots of 0.8 µl (160 ng/spot of rabeprazole and 1200 ng/spot of itopride hydrochloride) were applied on the precoated silica gel G60 F₂₅₄ TLC plate. From the peak area, the amount of rabeprazole and itopride hydrochloride in formulation was simultaneously calculated using the respective calibration graph. The amount obtained per tablet and percentage label claim are shown in Table 1.

The method was validated for linearity, accuracy, limit of detection, limit of quantification, inter-
day and intra-day assay precision, repeatability of measurement and repeatability of sample application. Samples were applied, the plate was developed with the mobile phase and the peak areas were noted. The mobile phase consisted n-butanol, toluene and ammonia (8.5:0.5:1 v/v/v), gave R_f values of 0.23 for rabeprazole and 0.75 for itopride hydrochloride. A good linear relationship was obtained over the concentration range of 40-200 ng/spot of rabeprazole and 300-1500 ng/spot of itopride hydrochloride, respectively. The linear regression data showed a regression co-efficient of 0.99848 for rabeprazole and 0.99030 for itopride hydrochloride. The repeatability of sample application and measurement of peak area were expressed in terms of %RSD for n=3 observation. The study revealed intra and inter day variation of rabeprazole and itopride hydrochloride are expressed in percentage RSD as shown in Table 1.

The LOD with signal/ noise ratio were found to be 10 and 50 ng/spot for rabeprazole and itopride hydrochloride respectively. The LOQ with signal/ noise ratio was found to be 20 and 100 ng/spot for rabeprazole and itopride hydrochloride, respectively. Intra-day assay precision was found by analysis of standard drug at three times on the same day. Inter-day assay precision was carried out using the standard drug at three different days, and percentage relative standard deviation (% RSD) was calculated. The RSD was found to be less than 2 for both inter-day and intra-day assay precision. Repeatability of sample application was assessed by spotting 0.8 µl of drug solution, 6 times. From the peak areas, the percentage RSD was determined.

Repeatability of measurement was determined by spotting 0.8 µl of standard drug solution on TLC plate, after development, spot was scanned six times without

TABLE 1: RESULTS OF ANALYSIS OF FORMULATION

Drug	Amount (mg/tablet)		% label claim±SD*
Drug	Labelled	Estimated	% label claim±SD*
Rabeprazole	20	19.60	98.41±0.1871
Itopride HCl	150	149.91	99.94±0.4557

*Mean±standard deviation of six determinations

Parameters	Rabeprazole	Itopride Hcl
LOD (ng/spot)	10	50
LOQ (ng/spot)	20	100
Linearity(ng/spot)	40-200	300-1500
Correlation coefficient	0.99848	0.99030
% Recovery studies
50%±SD	101.04±0.41	100.61±0.52
100%±SD	100.80±0.37	99.19±0.24
Precision
Intraday (%RSD)	0.7010	0.3373
Interday (%RSD)
1^st day	0.8247	0.8748
2^nd day	1.2803	1.3287
Repeatability of application	0.2494	0.2702
Repeatability of measurement	0.7510	0.3505

SD= Mean±Standard deviation of six determinations. Recovery study was performed for one formulation only. % RSD= Percentage relative standard deviation.

changing its position. The percentage RSD was found to be within the limits. The recovery study was carried out at two levels, 50% and 100%. The complete validation parameters are shown in Table 2.

Hence the developed HPTLC technique is simple, precise, specific and accurate, statistical analysis proved that the method is repeatable and selective for simultaneous analysis of rabeprazole and itopride hydrochloride as bulk drugs and in pharmaceutical dosage forms without any interference from the excipients.

Acknowledgments

The authors are grateful to M/s SNR and Sons Charitable Trust, Coimbatore, India, for providing the facilities to carry the experiment and Grandix Pharmaceuticals Ltd, Chennai and Abbott Laboratories, Goa, for providing gift samples of rabeprazole and itopride hydrochloride.

References

1. Budavari S, editors. The Merck index. 13th ed. Whitehouse Station, NJ: Merck and Co, Inc; 2001. p. 1450.

2. Kaul N, Agarwal H, Maske P, Rao JR, Mahadik KR, Kadam SS. Chromatographic determination of itopride hydrochloride in the presence of its degradation products by RP-HPLC. J Sep Sci 2005;28:1566-76.
3. Taisei M, Satio T, Mizutani F, Yamauchi T, Lwanga Y. The involvement of flavin containing monooxygenase but not CYP3A4 in metabolism of itopride hydrochloride a gastro prokinetic agent. J Pharmacol Exp Ther 2003;306:787.

4. Trivedi C, Soni K, Khan IT, Loya P, Saraf MN. High performance liquid chromatographic analysis with ultra violet detection for the determination of domperidone in human plasma. Indian Drugs 2005;42:461.

5. Zarapkar SS, Kanyawar NS. Simultaneous estimation of domperidone and omeprazole in pharmaceutical dosage by reverse phase high performance liquid chromatography. Indian Drugs 2002;39:217.
6. Takahara E, Fukuoka H, Takagi T, Nagata O, Kato H. Simultaneous determination of a new gastro intestinal prokinetic agent and its metabolites in human serum and urine by RP-HPLC. J Chromatogr B

1992;576:174-8. 7. Jain M, Shah L, Gupta S. Quantitation of itopride hydrochloride in human serum by HPLC with fluorescence detection and its application to bioequivalence study. J Chromatogr B 004;813:247.
8. Jinchang H, Yuxu SG, Lei L. Development of a liquid chromatography/ tandem Mass spectrometry assay for the quantification of rabeprazole in human plasma. J Chromatogr B 2005;19:2321.

9. Mondal U, Ganesan M, Pal TK, Jayakumar M, Chattaraj TK, Roy K, et al. Bioequivalence study of rabeprazole sodium on healthy human volunteers. J Indian Med Assoc 2004;102:26,28,30.

Microbiological Contamination Control in Pharmaceutical Clean Rooms

2008-12-16T09:42:00.003+05:30

Contamination control in pharmaceutical clean rooms has developed from a jumble of science and engineering, knowledge of what has worked well or badly in the past, dependent upon the technology available at the time the clean room was built and subsequent technological developments. Surrounding it all is a blanket of regulations. Taking a multidisciplinary approach, Microbiological Contamination Control for Pharmaceutical Clean Rooms neatly clarifies some of the perceived problems surrounding contamination control in pharmaceutical industry clean rooms. The book helps you satisfy domestic and international regulations and prevent your organization from suffering the consequences of non-compliance. It includes up-to-date information on microbiological contamination in sterile manufacturing, microbiological media fills, microbiological environmental monitoring, control in aqueous-based, non-sterile pharmaceuticals, rapid testing methods, and clean room contamination control. This valuable guide brings you up to date on the types of techniques available, the scientific principles that underpin them, and the practicalities and limitations of each.

This book neatly clarifies some of the perceived problems surrounding contamination control in pharmaceutical industry clean rooms. It helps manufacturers satisfy both domestic and international regulations and prevent their companies from suffering the consequences of non-compliance. It includes up-to-date information on microbiological contamination in sterile manufacturing, microbiological media fills, microbiological environmental monitoring, control in aqueous-based, non-sterile pharmaceuticals, rapid testing methods, and clean room contamination control. This book is an important resource for the microbiologist working in pharmaceutical manufacturing.

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2008-12-16T09:39:00.000+05:30

Raman spectroscopy has advanced in recent years with increasing use both in industry and academia. This is due largely to steady improvements in instrumentation, decreasing cost, and the availability of chemometrics to assist in the analysis of data.

Pharmaceutical applications
of Raman spectroscopy have developed similarly and this book will focus on those applications. Carefully organized with an emphasis on industry issues, Pharmaceutical Applications of Raman Spectroscopy, provides the basic theory of Raman effect and instrumentation, and then addresses a wide range of pharmaceutical applications. Current applications that are routinely used as well as those with promising potential are covered. Applications cover a broad range from discovery to manufacturing in the pharmaceutical industry and include identifying polymorphs, monitoring real-time processes, imaging solid dosage formulations, imaging active pharmaceutical ingredients in cells, and diagnostics.

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Handbook of Pharmaceutical Analysis (Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs)

2008-12-16T09:34:00.003+05:30

With nearly 2,000 references and more than 300 tables, equations, drawings, and photographs, the Handbook of Pharmaceutical Analysis is an invaluable source for analytical, bioanalytical, pharmaceutical, organic, clinical, medicinal, physical, quality control, and process chemists and biochemists; pharmaceutical scientists; and upper-level undergraduate and graduate students in these disciplines.

Contents
Form Selection of Pharmaceutical Compounds
Preparation of Drug Samples for Analysis
High-Performance Liquid Chromatography
Mass Spectrometry in Pharmaceutical Analysis
Ultraviolet Visible Spectroscopy
Immunoassay Techniques
Applications of Capillary Electrophoresis Technology in the Pharmaceutical Industry
Atomic Spectroscopy
Luminescence Spectroscopy
Solid-State Nuclear Magnetic Resonance Spectroscopy
Vibrational Spectroscopy
Statistical Considerations in Pharmaceutical Process Development

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Practice and Principles of Pharmaceutical Medicine

2008-12-16T09:27:00.001+05:30

This is an international guide to all areas of drug development and medical aspects of marketing. Both the regulatory and scientific aspects of the speciality of pharmaceutical medicine have evolved rapidly in recent years and Principles and Practice of Pharmaceutical Medicine assesses the current status of the field as well as giving some prospectus of how things may develop in the future. provides a refresher for the expert and an essential foundation for the novice outlines an academic framework for good practice This is an excellent source of information for all those practising pharmaceutical medicine - pharmaceutical physicians, regulatory physicians, clinical researchers, marketing executives, research nurses. It covers essential information for those studying for diplomas in pharmaceutical medicine and related fields and for specialists fulfilling requirements for continuing medical education. Includes: Overview of Pharmaceutical Medicine Pharmaceutical medicine as a medical speciality What pharmaceutical medicine is and who does it Competency-based training system for clinical research staff Drug Discovery and Development Pharmaceutics Informed consent Good Clinical Practices Drug Registration US Regulations Japanese Regulations Ethnic Issues in Drug Registration Medical Services Drug Surveillance Publishing Clinical Trials Legal and Ethical Aspects Pharmaceutical product liability Patents Business Aspects Financial Principles of clinical trials Third World Multinational Corporations.

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Official Methods of Analysis of AOAC International, 16th Ed.

2008-12-16T09:21:00.001+05:30

Official Methods of Analysis of AOAC International, 16th Edition.

The most comprehensive and reliable collection of chemical and microbiological methods available. For 122 years, AOAC has been meeting the need of analytical scientists for confidence in analytical results through the development and validation of AOAC® Official MethodsSM.

Part1
Part2
Part3
Part4

Spectrophotometric and HPLC Methods for Simultaneous Estimation of Pseudoephedrine Hcl and Loratadine from Tablets

2008-12-15T16:44:00.001+05:30

Two simple, accurate, economical and reproducible UV spectrophotometric and one HPLC method for simultaneous estimation of two-component drug mixture of pseudoephedrine hydrochloride and loratadine in combined tablet dosage form have been developed. The first developed method employs multiwavelength spectroscopy using seven mixed standards and 257.0 nm and 283.0 nm as two wavelengths for estimation. The second method involves first derivative spectroscopy using 308.6 nm and 263.0 nm as zero crossing points for pseudoephedrine hydrochloride and loratadine respectively. For both spectrophotometric methods, 0.2 M hydrochloric acid was used as solvent. Linearity was observed in concentration range of 0-40 μg/ml of loratadine and 0-800 μg/ml of pseudoephedrine hydrochloride. Developed HPLC method is reverse-phase chromatographic method using Inertsil C18 column and methanol:ammonium acetate buffer in ratio of 80:20 pH 7.5 as mobile phase. Nimesulide was used as internal standard for HPLC method. For HPLC method, linearity was observed in concentration range of 0-200 μg/ml of loratadine and 100-2000 μg/ml of pseudoephedrine hydrochloride. Results of analysis were validated statistically and by recovery studies.

Pseudoephedrine hydrochloride, chemically 2-methylamino-1-phenyl-1-propanol hydrochloride, has sympathomimetic activity1 and is official in the United States Pharmacopoeia2, British Pharmacopoeia3 and Indian Pharmacopoeia4. All the three pharmacopoeia describe HPLC method for estimation of pseudoephedrine hydrochloride from tablet formulation. Several chromatographic methods are reported for estimation of pseudoephedrine hydrochloride5-9 from pharmaceutical formulation. Loratadine, chemically 4-(8-chloro-5,6-dihydro-11-H-benzo-[5,6]cyclohept-al[1,2-b]pyridin-11-ylidene)-1-piperidine carboxylic acid ethyl ester, is an antihistaminic agent10 and is yet not official in any of the pharmacopoeia. Several methods are reported for estimation of loratadine11-18 from pharmaceutical formulations; however, none of the method is reported for simultaneous estimation of two drugs.

Developed spectrophotometric and HPLC methods are simultaneous methods of analysis of pseudoephedrine hydrochloride and loratadine from combined tablet dosage form. The developed methods were found to be simple, rapid, accurate, reproducible and economical. These methods can be used successfully for quality control testing of the drugs from combined tablet dosage form.

Materials and Methods:

Standard bulk drug sample of pseudoephedrine hydrochloride, loratadine and nimesulide were provided by Ranbaxy Laboratories Ltd., Dewas. Tablets of combined dosage form were procured from the local market. All other reagents used were of analytical grade for spectrophotometric methods and of HPLC grade for HPLC method.

Shimadzu UV/V is spectrophotometer (model-160 A) with

1 cm matched quartz cells was used for spectrophotometric methods. Spectra’s were recorded using specific program of apparatus, having specifications as follows: spectral bandwidth 3 nm, wavelength accuracy ±0.5 nm, wavelength readability 0.1 nm increments. For HPLC method, Shimadzu delivery module LC-10AD with UV SPD-10A detector and Chromatopac C-R7A integrator were used.

Method I—Multiwavelength spectroscopy:

Using the overlain spectra of pseudoephedrine hydrochloride and loratadine in 0.2 M HCl, the wavelength maxima of both drugs, i.e., 257.0 and 283.0 nm, were selected as two sampling wavelengths for this method. Seven mixed standards of two drugs in 0.2 M HCl were prepared so as to contain 0-600 μg/ml of

pseudoephedrine hydrochloride and 0-25 μg/ml of loratadine. All mixed standard solutions were scanned over the range of 400 nm to 220 nm in multicomponent mode of spectrophotometer using 257.0 nm and 283.0 nm as two sampling wavelengths. The spectral data from these scan were used to determine the concentration of two drugs in the sample solution.

Analysis of commercial formulation:

Twenty tablets were accurately weighed and average weight per tablet determined. Tablets were grounded to fine powder, and weighed tablet powder equivalent to 120 mg pseudoephedrine hydrochloride was transferred to 100 ml volumetric flask. The powder was extracted four times with 20 ml portions of methanol. The extract was collected in 100 ml volumetric flask after filtration through Whatman filter paper no. 41. The filter paper was washed with 20 ml methanol, and the washing was added to the filtrate. The methanol was evaporated on water bath and the residue was dissolved in 75 ml of 0.2 M HCl and again filtered through Whatman filter paper No. 41. The filter paper was washed with 20 ml of 0.2 M

HCl and the washing was added to the filtrate. The volume of filtrate was made to 100 ml mark with 0.2 M

HCl. In 10 ml volumetric flask, 2.5 ml of filtrate was taken and diluted to the mark with 0.2 M HCl.

The sample solution was scanned over the range of 400 nm to 220 nm in multicomponent mode and concentration of each component was estimated by analysis of spectral data of sample solution with respect to that of mixed standards by the instrument. Results of analysis are reported in Table 1.

Method II—First derivative spectroscopy:

From first derivative spectra of pseudoephedrine hydrochloride and loratadine in 0.2 M HCl zero crossing points, 308.6 nm and 263.0 nm were selected for simultaneous estimation of two drugs. Accurately weighed

TABLE 1: RESULTS OF ANALYSIS OF COMMERCIAL

FORMULATION

Method	Label Claim (mg/tablet)		% of Label Claim		Standard
	Label Claim (mg/tablet)		Estimated *	Deviation	Standard
	PS	LR	PS	LR	PS	LR
Method I	120	05	101.06	99.54	0.140	1.128
Method II	120	05	100.73	98.06	1.120	0.785
Method III	120	05	101.79	98.90	0.155	0.376

*Average of five determinations

pure drug sample of pseudoephedrine hydrochloride and loratadine were dissolved in 0.2 M HCl and were diluted with same so as to give several dilutions in the range of 0-800 μg/ml of pseudoephedrine hydrochloride and 0-30 μg/ml of loratadine. The absorbance of these dilutions were recorded in first derivative mode at 308.6 nm for estimation of loratadine, and 263.0 nm for estimation of pseudoephedrine hydrochloride. Respective calibration curves were prepared. Validity of proposed method was checked by preparing five mixed standards containing different concentrations of pure drug sample of pseudoephedrine hydrochloride and loratadine. Absorbance was measured at respective selected zero crossing points, and concentration of two drugs, using respective calibration curve, was determined. Validation studies gave satisfactory results.

Analysis of commercial formulation:

Tablet sample was prepared in similar manner as for Method I. Absorbance of final dilution of sample was

recorded at 308.6 nm and 263.0 nm from first derivative spectra of sample and amount of two drugs calculated using respective calibration curve. Results of analysis are reported in Table 1.

Method III—High-performance liquid chromatographic method:

HPLC method was developed using Inertsil C18 ODS 3V(5μ) 250 × 4.6 mm column. Mobile phase selected for this method contained 20 parts of ammonium acetate buffer (3.85 g/l) and 80 parts of methanol adjusted to pH 7.5 with sodium hydroxide that was filtered through 0.2 micron membrane filter. Flow rate employed was 1.0 ml/min. Detection of eluent was carried out at 250 nm and AUFS was set at 0.032. Method was developed using nimesulide as internal standard.

Standard stock solution:

Standard stock solutions of pure drugs were made separately in mobile phase containing 2000 μg/ml of pseudoephedrine hydrochloride, 200 μg/ml of loratadine and 100 μg/ml of nimesulide and filtered through a 0.2 micron membrane filter.

Preparation of calibration curve:

For preparation of the drug solutions for the calibration curves, in a series of 10 ml volumetric flasks, 1, 2, 3, 4 and 5 ml of the pure drug standard stock solutions of pseudoephedrine hydrochloride and 0.5, 1.0, 1.5, 2.0 and 2.5 ml of the pure drug standard stock solutions of loratadine were transferred. In each flask, 2.0 ml of stock pure drug solution of nimesulide was added and the volume was made up to the mark with the mobile phase. Each solution was injected and a chromatogram was recorded. Mean retention time for pseudoephedrine hydrochloride was found to be 3.158 min, for loratadine 13.464 min, and for nimesulide 4.440 min.

The peak area ratios of pseudoephedrine hydrochloride to nimesulide and loratadine to nimesulide were calculated and respective calibration curves were plotted against concentration of drug and peak area ratio of drug to internal standard.

Procedure for analysis of formulations:

Twenty tablets of the formulation were weighed and the average weight per tablet was calculated. Twenty tablets were crushed and ground to a fine powder. Powder equivalent to 240 mg of pseudoephedrine hydrochloride was weighed and transferred to a 100 ml volumetric flask containing about 75 ml mobile phase. To this volumetric flask, accurately weighed 10 mg of pure standard nimesulide was added. The powder mixture was dissolved in the mobile phase with the aid of ultrasonication. The solution was filtered through Whatman filter paper no. 41 into another 100 ml volumetric flask. The filter paper was washed with mobile phase and washings were added to the filtrate. Volume of filtrate was made up to the mark with the mobile phase. To another 10 ml volumetric flask, 2.0 ml of this solution was transferred and the volume was made up to the mark with the mobile phase. This solution was filtered through a 0.2 m membrane filter.

After setting the chromatographic conditions and stabilizing the instrument to obtain a steady baseline, the tablet sample solution was loaded in the 20 μl fixedsample loop of the injection port. The solution was injected and a chromatogram was recorded. The injections were repeated five times and the peak areas were recorded. A representative chromatogram has been given in Fig. 1. The peak area ratios of each of the drugs to the internal standard were calculated and the

Fig. 1: Chromatogram of pseudoephedrine hydrochloride, loratadine and internal standard nimesulide

amount of each drug present per tablet was estimated from the respective calibration curves. The results of analysis are presented in Table 1.

Recovery studies:

To study the accuracy, reproducibility and precision of the above methods, recovery studies were carried out by addition of standard drug solution to pre-analyzed sample at three different levels. Results of recovery studies were found to be satisfactory and are reported in Table 2.

Results and Discussion

The proposed methods for simultaneous estimation of pseudoephedrine hydrochloride and loratadine in combined tablet dosage form were found to be simple, accurate, rapid and economical. The values of coefficient of variance were satisfactorily low and recovery was close to 100%, indicating reproducibility of the methods. First method involving multiwavelength spectroscopy is specific to instrument having software for provision of

TABLE 2: RESULTS OF RECOVERY STUDIES

Method	Conc. Added (mg/ml)		% Conc. Recovered*
Method	PS	LR	PS	LR
	100	05	98.80	101.61
Method I	200	10	101.42	100.67
	300	15	100.88	98.69
	100	05	98.65	99.68
Method II	200	10	98.79	100.23
	300	15	99.76	98.26
	100	10	99.98	97.44
Method III	200	20	98.87	100.78
	300	30	100.80	98.08

*Average of three determinations

such determination. Selection of proper sampling wavelengths and concentration of components in mixed standard is critical. Since calculations are done by the instrument itself, chances of manual error are nil; furthermore, the method is quite rapid. Second method involving first derivative ultraviolet spectroscopy requires recording spectrophotometer with data processing mode. Proper selection of zero crossing point in derivative spectra completely eliminates the interference of unwanted component, and thus, concentration of two components can be easily calculated without prior separation of components from combined dosage form.

Third developed method for simultaneous estimation of two drugs from combined dosage form is reverse phase chromatographic method utilising C18 column and methanol ammonium acetate as mobile phase. Detection of eluent was carried out using UV detector. The method was developed using nimesulide as internal standard. The run time per sample is just 15 min. The excipients in the formulation did not interfere in the accurate estimation of pseudoephedrine hydrochloride and loratadine.

Since none of the methods is reported for simultaneous estimation of pseudoephedrine hydrochloride and

loratadine from combined dosage form, these developed methods can be used for routine analysis of two components without prior separation.

Acknowledgments

The authors would like to acknowledge Ranbaxy Laboratories Ltd., Dewas, India, for providing pure drug samples of pseudoephedrine hydrochloride, loratadine and nimesulide. Acknowledgment is further extended to Core Health Care Ltd., Rajpur, India, for providing facilities to carry out HPLC work.

References

1. Budavari, S., Eds., In; The Merck Index, 12th Edn., Merck and Co., Inc., Whitehouse Station, NJ, 1996, 3647.

2. United States Pharmacopoeia, 18th Edn., USP Convention Inc., Rockville, MD, 1995, 1339.

3. British Pharmacopoeia, Vol. II, Her Majesty’s Stationary office, British Pharmacopoeia commission, London,1993,1085.

4. Indian Pharmacopoeia, Vol. II, Government of India, The controller of Publication, New Delhi, 1996, 641.

5. Dash, A.K., J. Pharm. Biomed. Anal., 1998, 121, 601.

6. Fong, G.W. and Eickhoff, W.M., Int. J. Pharm., 1989, 53, 91.

7. Maierdan Wang, J.H., Yan, F.Z., Jin, Y., Cui, Y.Q. and Sun, D.J., Yaowu Fenxi Zazhi, 1994, 14, 27.

8. Noggle, F.T. and Clark, C.R., J. Assoc. Off. Anal. Chem., 1984, 67, 198.

9. Paeeran, M.T., Baravani, G.S. and Bhalla, V.K., Indian Drugs, 1988, 25, 242.

10. Budavari, S., Eds., In; The Merck Index, 12th Edn., Merck and Co., Inc., Whitehouse Station, NJ, 1996, 953.

11. El-Ragehy, N.A., Badaway, A.M. and Khateeb, S.Z., through Anal. Abstr., 1995, 28, 2363.

12. Kovas, E.M., J. Chromatogr., 1995, 692, 103.

13. Lin, Z.H., Yaowu Fenxi Zazhi, 1996, 16, 53.

14. Rajput, S.J. and Vyas, A.G., Indian Drugs, 1998, 35, 352.

15. Squella, J.A., Sturm, J.C., Diaz, M.A., Pessoa, H. and Nenuz-Vergora, L.J., Talenta, 1996, 43, 2029.

16. Vyas, A.G. and Rajput, S.J., Indian J. Pharm. Sci., 1997, 59, 186.

17. Zhang, D. and Blume, H., Pharmazie, 1994, 49, 736.

18. Zhong, D. and Blume, H., Pharmazie, 1994, 49, 730.

International Pharmacopoeia 3rd Edition

2008-12-15T13:54:00.002+05:30

Presents an historical account of the Pharmacopoeia and describes methods and procedures for the quality control of pharmaceutical substances and dosage forms, including a special section on quality control of anti-malarials.

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International Pharmacopoeia Volume 1

2008-12-15T13:46:00.003+05:30

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Quantitative Analysis of Propranolol Hcl by High Performance Thin Layer Chromatography

2008-12-15T12:26:00.003+05:30

A simple, accurate and precise HPTLC method has been developed for estimation of propranolol hydrochloride from bulk drug and tablet formulations. The separation was achieved on TLC plates using appropriate solvent system. The spots so developed were densitometrically scanned at 290 nm. The linearity of the method was found to be within the concentration range of 200-2000 ng/spot. The validation parameters, tested in accordance with the requirements of ICH guidelines, prove the suitability of this method. The method was successively applied for determination of drug in tablets, wherein, no interference from tablet excipients was observed.

Propranolol hydrochloride, chemically 1-[(1-methylethyl) amino] - 3 - (1 -naphthylenyloxy) -2-propranolol hydrochloride¹, is a non-selective β-adrenergic antagonist. It is used in the management of hypertension, phaeochromocytoma, angina pectoris, myocardial infarction and cardiac arrhythmias². Literature reported several titrimetric³,complexation⁴and spectrometric⁵ methods for analyzing propranolol. Several HPLC methods have also been reported for determining propranolol in pharmaceutical formulations and in biological fluids^6-14. Indian Pharmacopoeia describes a spectrometric method¹⁵, whereas, USP describes a HPLC method¹⁶ for assaying the drug. Following description is of a rapid, reliable and accurate HPTLC method for determination of
propranolol hydrochloride in tablets.

All chemicals used were of analytical reagent grade, purchased from M/s Qualigens Fine Chemicals Ltd., Mumbai, India. The tablets were procured from the local market. HPTLC system consisted of Camag Linomat V applicator (Muttenz, Switzerland), a Camag twin trough TLC chamber of appropriate size, Camag TLC scanner 3, Wincats software (version 1.3.0.) and a Hamilton syringe (Switzerland) of 100 µl capacity.

Chromatography was performed on 20×10cm aluminium backed silica gel 60 F_{254 TLC} plates (Merck, Darmstadt, Germany). Samples, applied as solutions of appropriate concentrations using Hamilton micro syringe and Linomat V applicator (Camag, Muttenz, Switzerland) were 6 mm wide bands with a distance of 13 mm within each spot. The plate was developed by ascending movement of solvent system, for 70 mm from the point of application, in a Camag twin trough chamber which was previously saturated with vapors of solvent system for a pre-optimized time period of 20 min at 25°±2°. The solvent system consisted of isopropanol: ethyl acetate:ammonia (1:8.5:0.5 v/v/v). The plate was dried and scanned at 290 nm, using Camag TLC scanner 3, equipped with Wincats software version 1.3.0., and slit dimensions of the scanner being set at 6.00 × 0.45 mm.

A stock solution containing 200 µg/ml of propranolol hydrochloride was prepared in methanol. Aliquots
of this solution were applied on the plates to give spots with concentrations of 200-2000 ng/spot. Each concentration was applied six times and developed as described above. Chromatograms were obtained representing sharp and symmetrical peak. Calibration curve was established by plotting the obtained peak area on ordinate against corresponding concentration on abscissa.

To determine the content of the drug in solid dosage form, 20 tablets were accurately weighed, their average weight calculated and they were finely powdered. Powder equivalent to 40 mg of the drug was dissolved in methanol and sonicated for 20 min. The solution was filtered and diluted to 100 ml with the same solvent. An aliquot measuring 1 ml was diluted to 10 ml with methanol and this solution was appropriately applied on the plate to get approximately 400 ng/spot of the drug. The results obtained are summarized in Table 1. The method was validated as per ICH guidelines¹⁷.

A standard stock solution of the drug was applied on the plate so as to contain 200-2000 ng of propranolol hydrochloride per spot. The plate was developed, dried, and scanned as described above. All measurements were repeated 6 times for each concentration. Correlation coefficient (r) of the line, passing through all the points on a graph constructed by plotting mean of peak areas on ordinate against corresponding concentrations on ordinate, was found to be 0.9997 with slope 4.905.

Limit of detection (LOD) and limit of quantitation (LOQ) were studied to determine the sensitivity of the

TABLE 1: ASSAY OF PROPRANOLOL HYDROCHLORIDE IN TABLET

Label claim	40 mg
Amount found ±SD (n=6)	40.27±0.254 mg
% Label claim	100.68 %
% RSD	0.630

n is number of repetitions

developed method. LOD was calculated using formula, LOD= 3.3×σ/S, where, σ is residual standard deviation of regression line and S is slope of corresponding line. The LOD and LOQ were found to be 59.72 ng and 180.97 ng of the drug, respectively. To ensure accuracy of the method, recovery studies
were performed by standard addition method at 80%, 100% and 120% level, to the pre-analyzed samples
and the subsequent solutions were re-analyzed. At each level, three determinations were performed and
the results obtained are shown in Table 2. The results of recovery studies were within the specified limits of

ICH guidelines. Lower values of % RSD reflect the accuracy of the method.

Precision, expressed in terms of % RSD, was determined in terms of intra-day and Inter-day precisions, analyzing the drug at three different concentrations, determining each concentration thrice. The sample solutions were analyzed using the method for 3 consecutive days, repeating the process twice-a-day at different period. The results obtained are summarized in Table 3, and reflect high degree of precision.

Two different analyst performed assay on marketed tablets of the drug, in similar operational and environmental conditions, using the developed method to determine its ruggedness, and the results are

TABLE 2: RESULTS OF RECOVERY STUDIES

Drug added (ng)	% Recovery n=3	Amount recovered (ng)±SD	% RSD
320	100.61	321.97±1.155	0.359
400	99.97	399.87±1.938	0.485
480	99.96	479.83±2.040	0.425

n is number of repetitions

TABLE 3: PRECISION OF THE METHOD

Amount applied (ng)	Intra-day precision (% RSD) n=3	Inter-day precision (% RSD) n=3
400	0.535	0.459
800	0.145	0.148
1200	0.051	0.077

n is number of repetitions

TABLE 4: RUGGEDNESS TEST FOR THE METHOD

Parameter (n=6)	Analyst 1 (n=6)	Analyst 2
Amount applied (ng)	400	400
Amount found (ng)	401.57	401.46
% RSD	0.273	0.287

n is number of replicates

Fig. 1: A typical chromatogram of propranolol hydrochloride scanned at 290nm

Fig. 2: A typical absorption spectrum of propranolol hydrochloride scanned at 200-400nm

summarized in Table 4. The optimized solvent system yielded a symmetrical peak for the drug with R_f0.52 (fig. 1). A typical absorbance spectrum of the drug is shown in fig. 2. The peak for the drug from tablets was identified by comparing the R_f,and also comparing its absorbance spectrum with that obtained with the standard drug. Peak purity was determined by co-relating the spectra of drug at peak start (s), peak apex (m) and at peak end (e) positions, (correlation r (s, m) = 0.9999, r (m, e) = 0.9997). Thus, it can be concluded that no impurities or degradation products, likely to be present in the marketed tablets, were found to interfere with the peak of the drug.

ACKNOWLEDGEMENT

The authors thank the Principal, Dr. S. J. Suarana, for providing necessary facilities, well in time, required during the process.

REFERENCES

1. Moffat AC, Osselton MD, Widdop B, Galichet LY. Clarkeís analysis of drugs and poisons. 3^rd ed. London: Pharmaceutical Press; 2004. p. 1495-7.

2. In: Sweetman SC, editor. Martindale- The complete drug reference. 33rd ed. London: Pharmaceutical Press; 2002. p. 962-3.

3. Basavaiah K, Chandrashekar U, Prameela HC, Nagegowda P. Titrimetric and spcetrometric determination of propranolol hydrochloride using chloramine-T. Indian Drugs 2004;41:303-5.

4. Basavaiah K, Chandrashekar U, Charan VS. Application of precipitation and complexation reactions for the analysis of propranolol hydrochloride. Indian J Pharm Sci 2003;65:161-6.

5. El-Eman AA, Belal FF, Moustafa MA, El-Ashry SM, El-Sherbiny DT, Hansen SH. Spectrophotometric determination of propranolol in formulations via oxidative coupling with 3-methylbenzothiazoline-2-one hydrazone. Il Farmaco 2003;58:1179-86.

6. Modamio P, Lastra CF, Montejo O, Marino EL. Development and validation of liquid chromatography methods for the quantitation of propranolol, metoprolol, atenolol and bisoprolol. Int J Pharm 1996;130:137-40.

7. Abdel-Hamid ME. Comparative LC-MS and HPLC analyses of selected antiepileptics and beta-blocking drugs. Il Farmaco 2000;55:136-45.

8. Spahn-Langguth H, Podkowik B, Stahl E, Martin E, Mutschler E. Improved enantiospecific RP-HPLC assays for propranolol in plasma and urine with pronethalol as internal standard. J Anal Toxicol 1991;15:209-13.

9. Lo MW, Silber B, Riegelman S. An Automated HPLLC method for the assay of propranolol and its basic metabolites in plasma and urine. J Chromatogr Sci 1982;20:126-31.

10. El-Sahart YS. Simultaneous high performance liquid chromatographic assay of frusemide and propranolol HCl and its application in a pharmacokinetic study. J Pharm Biomed Anal 2003;33:699-709.

11. 11. Rekhi GS, Jambhekar SS, Souney PF, Williams DA. A fluorometric liquid chromatographic method for the determination of propranolol in human serum/plasma. J Pharm Biomed Anal 1995;13:1499-505.

12. Wu ST, Chang YP, Gee WL, Benet LZ, Lin, ET. Stereoselective high performance liquid chromatography determination of propranolol and 4-hydroxypropranolol in human plasma after pre-column derivatization. J Chromatogr B 1997;692:133-40.

13. Ververs FFT, Schaefer HG, Lefevre JF, Lopez LM, Derendorf H.Simultaneous assay of propranolo, diltiazem and metabolites of diltiazem in human plasma by liquid chromatography. J Pharm Biomed Anal 1990;8:535-9.

14. Rumiantsev DO, Ivanova, TV. Solid-phase extraction on styrosorb cartridges as a sample pretreatment method in the stereoselective analysis of propranolol in human plasma. J Chromatogr B 1995;674:301-05.

15. Pharmacopoeia of India Vol. II, Government of India, Ministry of Health and Family Welfare, New Delhi: Controller of Publication; 1996. p. 635.

16. The United States Pharmacopoeia 27, The National Formulary 22, Bethesda, MD: United States Pharmacopoeial Convention, INC; 2004. p. 1587.

17. ICH Harmonised Tripartite Guideline, Validation of Analytical Procedures: Methodology, Q2B, 1996. p. 1-8.

A Validated HPTLC Method for Determination of Ondansetron in Combination with Omeprazole or Rabeprazole in Solid Dosage Form

2008-12-15T11:39:00.003+05:30

A simple, precise, accurate and rapid high performance thin layer chromatographic method has been developed for the simultaneous estimation of ondansetron combinations in solid dosage form with omeprazole and rabeprazole, respectively. The method involved separation of components by TLC on a precoated silica gel 60 F₂₅₄ using a mixture of dichloromethane:methanol (9:1) as a mobile phase. Detection of spots was carried out at 309 nm and 294 nm for ondansetron with omeprazole and ondansetron with rabeprazole combinations, respectively. The mean retardation factor for ondansetron and omeprazole were found to be 0.42±0.02, 0.54±0.03, respectively while for ondansetron and rabeprazole, 0.41± 0.02 and 0.51±0.02, respectively. The linearity and range was 0.1 to 0.5 µg/ spot for three drugs. The method was validated for precision, accuracy and reproducibility.

Ondansetron combination with proton pump inhibitors has recently been introduced in market for the treatment of peptic ulcer, gastroesophagal reflux disease (GERD) and to prevent nausea. Ondansetron antagonizes 5HT-3 receptor both peripherally as well as centrally and block the initiation of the reflux, so is used as antiematic. Ondansetron is official in USP¹. Omeprazole and rabeprazole are benzimidazole proton pump inhibitors, which suppress gastric acid secretion by H⁺/K⁺-ATPase enzyme system at the secretory surface of the gastric parietal cell. These drugs are used for the treatment of duodenal, gastric and esophageal ulceration. Omeprazole is official in USP¹, IP², BP³, where as rabeprazole is not official in any of the pharmacopoeia, but is reported in Merck Index⁴. Literature survey revealed HPLC^5,6 in human plasma, visible spectrophotometric method⁷ for ondansetron in solid dosage form. For omeprazole methods reported are HPLC-MS and HPLC-UV in biological fluids^8,9, capillary electrophoresis¹⁰, HPLC employing electrochemical and coulometric detection¹¹, TLC¹²and spectrophotometry¹³. For rabeprazole method reported are HPLC for detection in blood plasma^14,15spectrophotometric methods¹⁶, and LC-MS/MS¹⁷method. As no analytical method has so far been indicated for the ondansetron combinations with proton pump inhibitors, an attempt has been made to estimate them simultaneously by HPTLC.

Ondansetron reference standard was obtained as a gift sample from Neon Lab Ltd, Mumbai. Rabeprazole was obtained from Dr. Reddyís Lab, Hyderabad and omeprazole obtained from Zydus Cadila Health Care, Ahmedabad. Silica gel 60 F₂₅₄ TLC plates (20 × 10cm, layer thickness 0.2 mm, E. Merk, Mumbai) were used as a stationary phase. Dichloromethane:methanol (9:1) used as a mobile phase for both combinations. A Camag HPTLC system comprising of Camag linomat V semiautomatic sample applicator, Camag TLC scanner 3, Camag Win CATS software, Camag twin
trough chamber and a sonicator were used. Tablets containing omeprazole (10 mg) and ondansetron (4 mg) (Ranidom-O, Mankind Pharmaceuticals Pvt. Ltd., Mumbai, India) and capsules containing rabeprazole (20 mg) and ondansetron (6 mg) (OND-R, Besto Chemical Ltd., New Delhi, India) were used during study.

Working standards of ondansetron, omeprazole and rabeprazole (25 mg each) were weighed and diluted with methanol to get the final concentration 0.05 µg/ µl for omeprazole and 0.02 µg/µl for ondansetron and 0.05 µg/µl for rabeprazole and 0.015 µg/µl

for ondansetron. For ondansetron combination with rabeprazole, contents of twenty capsules was crushed to fine powder, quantity equivalent to 20 mg rabeprazole (6 mg ondansetron) was weighed accurately and transfer to 10 ml volumetric flask and for ondansetron combination with omeprazole, twenty tablets were crushed to fine powder, weight equivalent to 10 mg of omeprazole (4 mg of ondansetron) was transferred to 10 ml volumetric flask. Then to each flask about 5ml of methanol was added and sonicated for 15 min, finally volume was made to mark with methanol. The extracts were filtered through Whatman filter paper 41 and required dilutions were made to get the final concentration containing 0.05µg/µl rabeprazole, 0.015 µg/µl ondansetron and 0.05 µg/ µl omeprazole, 0.02 µg/µl ondansetron and 6 µl of standard and sample were applied as 5 mm band on the TLC plate.

TLC plates were prewashed with methanol and activated prior to use. The chromatographic conditions maintained were: Precoated Silica gel 60 F₂₅₄(20×10 cm) aluminum sheets as stationary phase. Dichloromethane:methanol (9:1 V/V) as mobile phase for both the ondansetron combinations. Samples were applied as bands 5 mm width at 14.1 mm intervals using Camag linomate V semiautomatic sample applicator and migration distance allowed was 80 mm, drying of plate done for 3 min at 60⁰ temperatures. The plates were scanned at 309 nm for omeprazole and ondansetron and 294 nm for rabeprazole and ondansetron combination with Camag TLC scanner III, using Camag Win CATS software (fig. 1).

Fig. 1: UV spectra of ondansetron in combinations UV spectra of ondansetron in combinations with (a) omeprazole and (b) rabeprazole, respectively

For calibration curve, 0.1, 0.2, 0.3, 0.4 and 0.5 µg/µl standard solution of omeprazole, rabeprazole and ondansetron were applied on TLC plate. The TLC plates were dried, developed and analyzed as described earlier.

Filtered solutions (6 µl) of the marketed formulations were spotted on to the plate followed by development scanning. The analysis was repeated six times, the spot was resolved into two peaks in the chromatogram of drug samples. The contents were calculated from the peak areas of standards and samples recorded.

A solvent system that would give dense and compact spots with appropriate and significantly different R_fvalues was desired for quantification of ondansetron combinations. The mobile phase consisting of dichloromethane: methanol (9:1 V/V) gave R_f value of 0.42±0.02, 0.54±0.03, respectively for ondansetron and omeprazole while for ondansetron and rabeprazole, 0.41± 0.02 and 0.51±0.02, respectively (fig. 2).

Fig 2: A typical HPTLC chromatogram of ondansetron combinations A typical HPTLC chromatogram of ondansetron combinations with (a) rabeprazole and (b) omeprazole, respectively in the marketed formulations

The developed method was validated in terms of linearity and range, limit of detection, limit of quantification, recovery study, inter days study, intra day study and study by different analysts. The limit of detection for omeprazole, ondansetron and rabeprazole, ondansetron was found to be 99 ng/spot, 39.9 ng/spot, and 90.3 ng/spot, 54.2 ng/spot, respectively. The limit of quantification for omeprazole, ondansetron and rabeprazole, ondansetron was found to be 302.8 ng/ spot, 121.1 ng/spot and 273.9 ng/spot, 164.4 ng/spot, respectively.

The linear regression data (n=6, Table 1) showed a good linear relationship over a concentration range 100 to 500 ng/spot for omeprazole, ondansetron and rabeprazole. Repeatability of method was determined by 6 times spotting 10 µl of standard drug solution on TLC plate, measurement of peak areas was performed and from the peak areas the % RSD was determined. For omeprazole and ondansetron % RSD was found to be 0.35 and 0.40, respectively and for rabeprazole and ondansetron % RSD was 0.19 and 0.45, respectively. Repeatability of measurement was determined by spotting 10µl of standard drug solution on TLC plate, after development the separated spots were scanned six times without changing position and % RSD for measurement of peak areas of omeprazole and ondansetron was found to be 0.64 and 0.80, respectively and for rabeprazole and ondansetron % RSD was 0.31 and 0.42, respectively.

TABLE 1: VALIDATION PARAMETERS

Parameters*	Omeprazole	Ondansetron	Rabeprazole	Ondansetron
Rf (±SD)	0.54±0.03	0.42±0.02	0.51±0.02	0.41±0.02
Linearity and range (ng/spot)	100-500	100-500	100-500	100-500
Limit of detection (ng/spot)	99	39.9	90.3	54.2
Limit of quantification (ng/spot)	302.8	121.1	273.9	164.4
Repeatability of application (%RSD)	0.35	0.40	0.19	0.45
Repeatability of measurement (%RSD)	0.64	0.80	0.31	0.42
Intra day (%RSD)	0.12	0.14	0.66	0.29
Inter day (%RSD)	0.77	0.58	0.23	0.54
Different analysts (%RSD)	0.21	0.61	0.14	0.72

*Average of 6 determinations

TABLE 2: ANALYSIS OF ONDENSETRON WITH OMEPRAZOLE (RANIDOM-O) AND ONDENSETRON WITH RABEPRAZOLE (OND-R)

Brand name	Drug	Label claim (mg/tab)	Amount found* (mg/tab)	% drug found*	% RSD
Ranidom-O	Ondensetron	4	3.99	99.90	0.45
	Omeprazole	10	10.039	100.39	0.49
OND-R	Ondensetron	6	5.99	99.96	0.82
	Rabeprazole	20	19.96	99.83	0.72

*Average value of 6 observations

The assay value for the marketed formulation was found to be within the limits as listed in Table 2. The low RSD value indicates suitability of the method for routine analysis of omeprazole, ondansetron and rabeprazole, ondansetron in pharmaceutical dosage form. Recovery studies were carried out to study accuracy and precision of the method. These studies were carried out at three levels i.e. multiple level recovery studies. To the powder formulations the pure standard drug were added at 80%, 100% and 120% levels, dilutions were made and analyzed by the method, the % recovery was calculated by using formula, % recovery = (T-A)/S × 100 where, T is total amount of the drug estimated, A is the amount of drug contributed by tablet powder and S is the amount of pure drug added. The results of recovery studies for both the ondansetron combinations were found to be around 99-100%, indicating that the method is free from interference from excipients.

The ruggedness of the method was evaluated by studying analyst to analyst, intra day and inter days variations and the % RSD was calculated, that was found to be within range. From the above results it can be concluded that the HPTLC method is accurate, precise, specific and reproducible and can be used for routine analysis of ondansetron combinations with proton pump inhibitors in solid dosage form.

ACKNOWLEDGEMENTS

The authors thank the Principal, Institute of Pharmaceutical Education and Research, Wardha and Anchrom Lab, Mumbai for providing facilities for the research work and Neon Lab Ltd for providing ondansetron, Dr. Reddyís Lab for providing rabeprazole and Zydus Cadila Health Care for providing omeprazole as gift sample for analysis.

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