Robustness of Analytical Chemical Methods and Pharmaceutical Technological Products

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

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

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

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

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

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

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

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

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

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

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

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

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)

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)

• 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

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)

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)

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

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

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

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

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

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

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

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

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

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

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.

Link (2 Parts)
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SAS Programming in the Pharmaceutical Industry

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)

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.


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

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^4-9 in 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

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^2-9 have 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 G60 F₂₅₄ 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*
	Labelled	Estimated
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)
1st day	0.8247	0.8748
2nd 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.