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Ajay D. Kshirsagar et al: Bioavailability and bioequivalence study

JPSI 2 (6), Nov-Dec 2013, 10-16

Journal of Pharmaceutical and Scientific Innovation www.jpsionline.com

Review Article

BIOAVAILABILITY AND BIOEQUIVALENCE STUDY IN CORRELATION OF BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS) AND POSSIBLE MODIFICATION Ajay D. Kshirsagar1*, Omkar N. Shikare2, Haidarali M. Shaikh2 1Department of Pharmacology, Faculty of School of Pharmacy, SRTM Nanded, India 2Padmashree Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, India *Corresponding Author Email: [email protected] DOI: 10.7897/2277-4572.02681 Published by Moksha Publishing House. Website www.mokshaph.com All rights reserved. Received on: 07/10/13 Revised on: 24/11/13 Accepted on: 28/11/13 ABSTRACT In the last decade, the regulatory bioequivalence (BE) requirements of drug products have undergone major changes. Now a day the bioavailability and bioequivalence study is emerging area in the generic world. Today, the discovery of drug substances with increasing lipophilicity and resultant poor aqueous solubility is a more and more common problem in the development of orally administered new formulations. The Biopharmaceutics Classification System (BCS) is the technique used to differentiate the drugs on the basis of their solubility and permeability is a guide for predicting the intestinal drug absorption. The knowledge of the BCS characteristics of a drug in a formulation can also be utilized by the formulation scientist to develop a more optimized dosage form based on fundamental mechanistic, rather than empirical, information. The possible changes in the class three and four drugs we increase the solubility and permeability and achieve great success in the field of generic market. Here in this review we compile the information on all four class drugs of BCS and their possible modification. Keywords: Bioequivalence, Bioavailability, Biopharmaceutics Classification System (BCS) INTRODUCTION The growth of the generic pharmaceutical industry has increased enormously during the last 10-25 years. This growth has been driven by a number of factors, in particular the need to contain public spending on health care, including drug products. The demand of generic drug product is intended as a substitute for innovator pharmaceutical company product must be 'equivalent'. When a generic drug product for an innovator drug product requires that the products must not only be pharmaceutically equivalent, but also bioequivalent. In general, for a generic product to be concerned as bioequivalent with the pioneer product, any difference in the rate and extent of absorption of the active moiety to the site of drug action must be judged to be clinically insignificant. The fundamental reason for performing bioequivalence testing is to ensure, as far as possible, the quality of generic drug products. In particular, such testing is intended to prove that there are not likely to be any differences in safety and efficacy between a generic and an innovator drug product; that is, that the products are therapeutically equivalent. Thus, in essence, bioequivalence is considered as alternate of therapeutic equivalence. Many countries have established the law that allows for the approval of generic products on the basis of the evidence of bioequivalence with an innovator product. The process usually involves the submission of an 'abbreviated new drug application' to the applicable drug regulatory agency. Such a submission must contain demonstration establishing bioequivalence, as well as pharmaceutical and other relevant information, but it need not contain preclinical (e.g. Toxicity) data or the full range of demonstration of clinical safety and efficacy, which is required within a full 'new drug application' for a pioneer product. In many countries, law controlling the approval of generic drug products has been happening by legal mechanisms to provide an motivator for pioneer pharmaceutical companies to undertake research and development of new drugs. A notable example is the Drug

Price Competition and Patent Term Restoration Act of 1984 (the so-called Waxman-Hatch Amendment of 1984) that amended the United States Federal Food, Drug and Cosmetic Act1. Bioavailability The rate and extent to which active ingredient is absorbed from a drug product and becomes available at the site of action. The drug product that is not intended to be absorbed into the bloodstream, bioavailability may be evaluated by measurements resulted to reflect the rate and extent to which the active ingredient becomes available at the site of action. One regulatory objective is to evaluate, through appropriately designed BA studies, the performance of the formulations used in the clinical trials that provide a demonstration of safety and efficacy (21 CFR 320.25 (d)1. Before marketing a drug product, the performance of the clinical trial dosage form can be possible, in the circumstances of evidencing safety and efficacy. The general exposure profiles of clinical trial material can be used as a benchmark for consequent formulation changes and can be useful as a reference for future BE studies. Although BA studies have many pharmacokinetics objectives beyond formulation performance as described above. We note that subsequent sections of this guidance focus on using relative BA (referred to as product quality BA) and in particular, BE studies as a means to document product quality. In vivo performance, in terms of BA/BE, can be conceived to be one aspect of product quality that provides a link to the performance of the drug product used in clinical trials and to the database containing a demonstration of safety and efficacy. Bioequivalence The term ‘Bioequivalence’ is defined as differently in each of the studied guidelines, although both guidelines refer to the same methods of PK analysis. It should also be observed that although numerous fragments of the AB Guideline are true


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copies of the HB guidelines, this does not apply to the definition. Other agencies and institutions that produce documents related to BE studies does not accept from this pattern. An example is the definition of BE presented by the World Health Organization (WHO)2. Moreover, the AB definition introduces information on finding of the active drug in the blood plasma. That is not an appropriate place for this type of elucidation especially considering BE studies conducted on the basis of not only the determination of drug concentration in blood plasma, but also in serum, whole blood, urine and tissues. CVMP advocates that pilot data would be yielded before to starting the pivotal study but AB guidelines does not provide details on how to plan pilot studies before the pivotal pharmacokinetic studies are conducted. Other agencies (e.g. Food and Drug Administration – FDA, and Health Canada – HC) have long treated this form of analysis as a preliminary to the proper optimization of BE study design3-5. Pilot studies are often utilized as a means for designing optimized BE studies. Pilot studies assist to identify inter- and/or intra-subject variability, and to verify the scope and the distribution of sampling points, as well as critical assigns of the Bioanalytical method such as the lowest limit of quantitation (LLOQ) and the highest limit of quantitation (HLOQ). Documents of some agencies (e.g. FDA) also reference pilot studies as an important element in identifying the flip-flop pharmacokinetics. An example is the FDA document that stresses the role of pilot studies in the analysis of this effect (FDA, 2006). This document gives great attention to the role of pilot studies in designing the appropriate BE studies of veterinary drugs2-6. Bioequivalence of two drug formulations is currently defined by drug regulatory authorities in terms of the mean responses (average bioequivalence) following administration of the test and reference formulations. The discovering that the average bioavailability of the test and reference formulation is similar does not mean that the bioavailability metrics of the test and reference product are similar in all or even most individuals. It has been discovered that the safety for the substitution of a reference drug product with a test drug product in patients, whose concentrations might have been titrated to a steady efficacious and safe level, could be a concern. Therefore, it is proposed that individual bioequivalence within each subject should be assessed to assure the safety of the drug switchability. Switchability actually demands that, within the same patient, the drug concentrations of the test formulation remain within the same therapeutic window achieved by the reference formulation. The statistical evaluation of the individual bioequivalence examines that the pharmacokinetics windows for the test and reference formulations are similar. The various potential shortcomings of average bioequivalence are now understood, and switchability, and thus individual bioequivalence, has become a reasonable expectation when changing from one pharmaceutically equivalent drug product to another. The advance has been made in developing criteria for individual bioequivalence, and a classification of most of the different approaches to the assessment of individual bioequivalence has been achieved. We review and discuss some technical statistical issues and practical execution issues associated with the use of individuals as opposed to population average bioequivalence to express the relative bioavailability of alternative formulations of a drug. During the last two to three decades, biopharmaceutics has been undergoing a revolution from drug discovery to drug

regulatory standards and harmonization. Biopharmaceutics is based on the chemical and physical properties of drug content, and the formulation, physiology of the route of administration. Nowadays, many particles are classified through screening processes, and promising candidates enter into drug pipelines for further in vitro and in vivo tests. At the end of the development process stands the approval by the regulatory agencies. From a strict economic point of view, this is the important step for moving from a drug candidate to a product which improves health and to cover the discovery costs. Some national and international societies and agencies are doing workshops and conferences to harmonize the standards and documentation needed for drug safety and quality1, but there is still work in front. Class I BCS class I drugs are defined as being highly soluble and highly permeable. For illustrate, metoprolol, propranolol, and theophylline are categorized into this class7. For BCS class I drugs, there should be no rate-limiting step for absorption of oral route. IR solid oral dosage forms, for example, capsule formulations or conventional tablet, are usually planned to ensure quick dissolution in the gastrointestinal tract. This class which helps the tablet easily pass first pass metabolism and there is less problem with the patient, related to adverse event and side effect compare to the other BCS class. Class II Nowadays, the discovery of drug substances with intensifying lipophilicity and outcome poor aqueous solubility is a more and more common problem in the development of orally administered Modern formulations. The majority of registered drugs falls into Biopharmaceutics Classification System (BCS) class II (high permeability, low solubility) or IV (low permeability, low solubility)8,9. For the BCS class II drugs, the oral absorption is mostly limited by the solubility and/or dissolution in the gastrointestinal (GI) tract. In such case, it should be of value to have an in vitro dissolution test that could be used to omen the in vivo behaviour during the various steps in formulation development. Biorelevant media simulating the fasted and fed states in the small intestine have been developed and utilized to increase the in vivo predictability10-12. These simplified media, called as fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF), contain the most important physiological amphiphiles, bile salts (BS) and lecithin (LC) and consider the pH, buffer capacity and osmolality of the gut lumen. To improve image the solubilization capacity in the fed state, digestion products, such as fatty acids and monoglycerides, have additionally been included in the media13–16. Class III Class 3 contains high solubility/low permeability drug substances. Hence, it is safe to consider that the intestinal permeability is considered to be the rate-controlling step in oral drug absorption. This shows that the absorption kinetics of BCS Class 3 drugs from the gastrointestinal (GI) tract could be controlled by the biopharmaceutical and physiological properties of the drug substance, rather than preparation factors, provided excipients do not affect drug permeability or drug intestinal large time. The assumptions that excipients do not affect drug permeability and intestinal transit time are significant assumptions that merit further


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investigation. Human studies to determine excipient effects in a dose-response fashion could be considered unethical, not practical, and cost prohibitory. In vitro culture studies using Caco-2 cells have been conducted to determine the effect of some common excipients. Cell culture methods are easily impacted by solvents used to make easier the solubility of drugs and or excipients due to volume limitations. In addition, studies clearly show that the behaviour of the gastrointestinal tract is controlled by immunological, neuronal and hormonal controlling mechanisms13. The failure of in vitro dissolution to predict bioavailability might be related to the principle of solute-solvent interactions and its influence on solubility and solubilization, which has been studying in large amount16–23. The Hildebrand–Scatchard model16,17 has been distanced to handle the solubility production of drugs in polar solvents.

Class IV The very great pharmaceutical research in understanding the causes of low oral bioavailability has led to the development of new technologies to address these challenges. One of the technologies is to design a prodrug with the required physical-chemical properties to improve the oral bioavailability15. The main technologies to achieve the increased oral bioavailability of drugs with poor aqueous solubility include the use of micronization, nanosizing, crystal engineering, solid dispersions, cyclodextrins, solid lipid nanoparticles and other colloidal drug delivery systems such as microemulsions, self-emulsifying drug delivery systems, self microemulsifying drug delivery systems and liposomes16,17. Currently, approximately 42 % of the marketed immediate release (IR) oral drugs are categorized as practically insoluble (<100 g/ml)18. Combinatorial chemistry and high-throughput screening used in drug discovery have resulted in an increase of poorly water soluble drug prospects22,23.

Table 1: BE Dissolution Proposal

BCS Class

Drug Solubility pH 1.2

Drug Solubility pH 6.8

Drug Permeability

Preferred Procedure

I High High High >85 % Dissolution in 15 min; 30 min, f2., pH = 6. 8.

II Low High High 15 minutes at pH=1.2, then 85 % Dissolution in 30 minutes, pH = 6.8; F2 > 50; 5 points minimum; not more than one point > 85 %.

III High High Low >85% Dissolution in 15 minutes, pH = 1.2, 4.5, 6.8. IV Low High Low 15 minutes at pH = 1.2; then 85 % Dissolution in 30

min., pH = 6.8,; F2 > 50; 5 points minimum.; not more than one point > 85 %.

Table 2: BCS Class Inferences

Solubility Permeability Absorption Rate

High High Well absorbed drugs. Controlled by Gastric Emptying for rapidly dissolving drug products. Cmax is the critical in vivo parameter*.

Low High The drug may be well absorbed. Controlled by Dissolution. Cmax is the critical in vivo parameter*. High Low Limited oral absorption. Controlled by High Low Permeability. Cmax and AUC critical in vivo parameters. Low Low Poorly absorbed. Cmax and AUC critical in vivo parameters.

Since high permeability drugs are rapidly absorbed, maximum plasma concentrations (Cmax), are indicative of overall AUC and long-duration in vivo studies is not required. In class four drugs have the low permeability and solubility drug. And some modification is necessary to improve these qualities such as. · Self-emulsification · Amorphization · Cyclodextrin complexation · pH modification · Particle size reduction Micronization Nanocrystals · Crystal modifications Metastable polymorphs Salt formation Cocrystal formation Self-emulsification In recent years, self-emulsification drug delivery systems (SEDDS) have been utilized to enhance the oral bioavailability of poorly water-soluble drugs, especially for highly lipophilic drugs. Self-emulsification formulations are isotropic mixtures of oil, surfactant, cosolvent, and

solubilized drug24. These formulations can quickly form oil in water (w/o) fine emulsions when dispersed in an aqueous phase under mild agitation. SEDDS are additionally classified into self-microemulsification drug delivery systems (SMEDDS) and self-nanoemulsification drug delivery systems (SNEDDS) according to the size range of their oil droplets25. SMEDDS form microemulsions ranging in droplet size from 100 to 250 nm. Finer microemulsions of less than 100 nm can be obtained using SNEDDS. The rapid emulsification of these formulations in the gastrointestinal tract can provide both improved oral bioavailability and a reproducible plasma concentration profile. The droplet size of the emulsion would influence the extent of absorption of the orally administered drugs. Neoral®, a cyclosporin SNEDDS formulation, is a good example of the effectiveness of the utilization of droplets of a smaller size. Neoral® showed increased Cmax and AUC compared with Sandimmune®, a coarse SMEDDS formulation, in human26. SEDDS would require a relatively high intrinsic lipophilicity of the drug substance since the active ingredient should be dissolved in a limited amount of oil. High chemical stability of the dissolved drug in oil phase would also be required for the lipid formulations.


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Amorphization Amorphous solids have higher energy than crystalline solids. Typically, the solubility of an amorphous drug is higher than that of the corresponding crystalline drug. The differences of the solubility between amorphous form and crystalline form have been reported to be between 1.1 and 1000-fold. The marked enhancement in the saturated solubility of amorphous drug may lead to a significant improvement of oral bioavailability. Stable amorphous formulations can be obtained by solid dispersion techniques. Amorphous solid dispersion (ASD) is defined as a distribution of active ingredients in molecular and amorphous forms formed by inert carriers27. The ASD formulations can be prepared by spray drying, melt extrusion, lyophilisation, and use of supercritical fluids with polymeric carriers and/or surfactant28. Numerous studies have demonstrated the marked enhancement of oral absorption by ASD approaches29-32. The ASD approaches were found to show 1.5–82-fold and 1.6–113.5-fold enhancements in Cmax and AUC compared with crystalline formulation containing bulk API or a physical mixture of API and carriers. The AUC enhancement ratio of the majority of the listed drugs was found to be less than 20-fold. However, a more than 20-fold improvement in the pharmacokinetic parameters was noticed in a few cases. ER- 34122 (Eisai) is a 5-lipoxygenase/cyclooxygenase inhibitor with low aqueous solubility (<10 ng/ml)33. Surprisingly, the amorphous formulation of ER-34122 showed ca. 200-fold enhancement in the solubility in JP 2 medium compared with ER- 34122 alone, and both Cmax and AUC after oral administration of the amorphous formulation were ca. 100 times higher than those of pure drugs in dog. Generally, ASD formulations tend to be chemically and physically less stable than the corresponding crystalline solid. The change from amorphous form in crystalline form in ASD formulation would lead to a reduction of oral bioavailability of the incorporated drugs. In contrast to the CSD formulations, the ASD approaches may be unsuitable for amorphous drugs with low stability. Cyclodextrin complexation Cyclodextrins are oligosaccharides containing a relatively hydrophobic central cavity and hydrophilic outer surface34. Cyclodextrins have been widely used in pharmaceutical product development, and there are currently more than 10 marketed cyclodextrin-containing solid dosage forms. Cyclodextrins and their derivatives enhance the apparent solubility of poorly water-soluble drugs by forming inclusion complexes. Numerous studies have shown the enhancement of the oral bioavailability of poorly water-soluble drug, goes by the cyclodextrin inclusion complex35. The physical mixture of drug and Cyclodextrins has been reported to show no or limited bioavailability enhancement after oral administration. However, enhanced bioavailability was noticed by forming a complex of drug and Cyclodextrins, and the AUC enhancement ratio by complication has been reported to be 1.1–46-fold matched with that of control formulations such as crystalline drugs and lyophilised drugs36. pH modification pH modification in solid dosage forms is assumed to be an alternative option for an ionizable drug to improve the solubility and dissolution rate. The pH change significantly influences the saturation solubility of an ionizable drug by

dissociation. The incorporation of pH modifiers in the dosage form can alter the microenvironmental pH. Microenvironment is a term used to represent a microscopic layer surrounding a solid particle in which the solid forms a saturated solution of adsorbed water37. The microenvironmental pH would affect the performance of the solid dosage form, such as the chemical stability of the drug substance and the dissolution profile38. There have been several studies evidencing the pH-independent release of basic drugs form controlled release dosage forms by using pH modification technologies39. However, the examples of application of pH modification system to IR formulation are few40. BMS- 561389 (razaxaban, Bristol-Myers Squibb) is a weak basic drug with a poor intrinsic solubility (˜0. 2 µg/ml). BMS-561389 showedan enhanced dissolution rate from IR tablet by incorporating tartaric acid in the tablet compared with that of the tablet without tartaric acid under non-sink condition (pH 5.5). Furthermore, the tartaric acid-containing tablets showed significant improvements in AUC and Cmax compared with the control tablets in famotidine pretreated dogs. These results suggested that pH modification in dosage form could reduce the variability in the absorption of administered drugs. The solubility, dissolution rate, and pKa of pH modifier would change the dissolution rate of the drug. To obtain the complete dissolution of the drug from dosage form, the pH modifier may need to coexist with the drug particles in tablet or granule until the containing drug is completely dissolved. Accordingly, the excipients and manufacturing methods would affect the dissolution performance of the drug from the pH-modified solid dosage forms. The estimation of the microenvironmental pH in the dosage form is thought to be helpful in designing pH-modified dosage forms. Particle size reduction Micronization Particle size reduction approach is broadly used to increase the dissolution rate as well as salt formation. The dissolution rate of a drug proportionally enhances with an enhancing surface area of drug particles41. According to the Prandtl boundary layer equation, the decrease of diffusion layer thickness by reducing particle size, particularly down to <5 µm, would result in accelerated dissolution42. Thus, the increased surface area and the decreased diffusion layer thickness would lead to an enhanced dissolution rate of the drug. Micronization approach successfully enhanced the bioavailability of poorly water-soluble drugs such as griseofulvin, digoxin, and felodipine43. The common method to obtain micronized drug particles is the mechanical crush of larger drug particles. Jet milling, ball milling, and pin milling are commonly used for dry milling. For solid powders, the lowest particle size that can be achieved by conventional milling is about 2–3 µm. The milling does not always result in significantly enhancing the dissolution rate of the drug. Micronization sometimes increases agglomeration of the drug particles, which may decrease the surface area available for the dissolution. In such case, wetting agents, such as a surfactant, would play a major role in increasing the effective surface area. Nanocrystals Particle size reduction to nano-meter range (<1 µm) is an attractive\ approach for poorly water-soluble drugs. Particle size reduction could lead to an increase of the surface area


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and a decrease of the diffusion layer thickness, which could provide an enhanced dissolution rate for drugs. In addition to these factors, an increase in the saturation solubility is also liked by reducing the particle size to less than 1 µm, as described by Ostwald–Freundlich’s equation44. The nanocrystal formulations are commonly produced by wet-milling with beads, high-pressure homogenization, or controlled precipitation45. Hydrophilic polymer and/or surfactant are typically used to stabilize nanocrystal suspension. The nanocrystalline drug particles are dispersed into inert carriers after a drying process, such as spray drying or lyophilization. Herein, the solidified nanocrystal formulations can be defined as crystalline solid dispersion (CSD). There have been numerous studies demonstrating the enhanced oral bioavailability of pharmaceuticals and neutraceuticals by nanocrystal technologies46. Nanocrystal formulations have been found to show 1.7–60-fold and 2–30-fold enhancement in Cmax and AUC compared with crystalline formulations with micrometer particle size. Crystal modifications Different physiological and formulation factors are responsible for the bioavailability of drugs from the dosage form. One of the most important physical factors, which affect the bioavailability and therapeutic efficacy of drug, is the existence of active ingredients in various crystal forms having different internal structure and physical properties47. The different crystal form of a drug has different physicochemical characteristics, namely crystal shape, crystal size, melting point, density, flow properties solubility pattern, dissolution characteristics and XRD pattern, though they are chemically identical. A physical form having an improved dissolution rate and solubility is useful for improving the bioavailability of a drug48,49. The crystal habit is an important variable in pharmaceutical manufacturing, where some factors, such as the polarity of crystallization solvent and the presence of impurities in the solvent, affect crystallization50-

52. Among them, solvent strongly affects the habit of crystalline materials; however, the roleplayed by solvent interactions in enhancing or inhibiting crystal growth is still not completely understood53. Metastable polymorphs Polymorphism in crystalline solids is defined as materials with the same chemical composition, but different molecular conformations54. The huge majority of drugs can be crystallized into several polymorphs. Each polymorph has a different energy, showing different physicochemical properties, such as melting point, density, solubility, and stability. Generally, the solubility of metastable polymorphs is kinetically higher than that of a thermodynamically more stable polymorph55. The differences of the solubility among polymorphs were reported to be typically less than 2.0-fold56. Although the practical purpose of metastable polymorphs is one of the effective approaches to enhance the dissolution rate of a drug, the metastable forms eventually convert to the thermodynamically stable form. It is necessary to monitor the polymorphic transformation during both manufacturing and storage of dosage forms to make certain of reproducible bioavailability after oral administration57. Salt formation

In the pharmaceutical industry, the salt formation approach is commonly used for an ionizable drug to increase solubility and dissolution rate. Salts are formed via proton transfer from an acid to a base. A stable ionic bond can be formed when the co-relate to peak between an acid and a base (peak) is greater than 358. The counter ion containing salt changes the pH in -the dissolving surface of a salt particle in the diffusion layer, resulting in a higher dissolution rate of the salts compared with that of the matching free forms59. According to the Henderson-Hasselbalch equations, the change of pH highly affects the aqueous solubility of an ionizable drug60. In theory, the solubility of a weak basic drug increases exponentially with decreasing pH in the pH range between its pKa and pHmax (pH of maximum solubility in the pH-solubility profile). The increased saturation solubility on the dissolving surface contributes to the higher the dissolution rate by salt formation. Celecoxib, a poorly water soluble weak acidic drug, showed an enhanced dissolution rate and oral bioavailability with a combination of Na salt formation and the use of a precipitation inhibitor compared with the corresponding free acid form61. The solubility and dissolution rate of salt are influenced by the counter ion containing the salt. The solubility of haloperidol mesylate was significantly higher than that of its hydrochloride salt at a lower pH range62. The aqueous solubility of a moderately soluble hydrochloride salt for a basic drug is sometimes reduced in a solution containing chloride ion, such as gastric fluids (common-ion effects). An appropriate salt form should be developed from the viewpoints of both physicochemical and biopharmaceutical properties, especially for poorly water-soluble drugs. Cocrystal formation In recent years, much attention has been drawn to cocrystal for changing the dissolution rate of poorly water-soluble drugs. Cocrystal is widely defined as crystalline materials exchanged of at least two different components63. Pharmaceutical cocrystal is typically composed of an API and a nontoxic guest molecule (cocrystal former) in a stoichiometric ratio. Unlike salt formation, proton transfer between the API and cocrystal former does not take place in cocrystal formation. In many cases, the API and cocrystal former require hydrogen bonding to form a stable crystal. Generally, pKa is one of the good indicators for distinguishing between salts and cocrystals, and the molecular complexes can be defined as a cocrystal when the pKa is less than zero58. When the pKa is between 0 and 3, they can be salts or cocrystals or can contain sheared protons or mixed ionization states that cannot be assigned to either category. There have been several studies demonstrating the increased dissolution rate and oral bioavailability by crystal formation64. AMG-517 (Amgen) is a potent and selective VR1 antagonist65. AMG-517 is a free base, but insoluble at physiological pH because there is no pKa value in the physiological range. The cocrystal of AMG 517 and sorbic acid proved a higher dissolution rate in the fasted state simulated intestinal fluid, and 9.4-fold enhancement in AUC0–Inf was observed compared with that of its free base form after oral administration to dog (500 mg/kg). In addition to other crystal engineering approaches, such as metastable polymorphs and salt formation, cocrystal approach could be an alternative option for improving the dissolution rate of poorly water-soluble drugs, especially for the drug candidates that are not ionized at physiological pH.


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CONCLUSION In the bioavailability and bioequivalence study the permeability and solubility parameter pay a great attention because any pharmaceutical company wants to achieve great position in the generic market. In this review add some modification technique such as complex formation, clathrets, and the addition of cyclodextrin addition we increase the BA and BE parameter. Researchers now focus on the modification of class for drug by introducing newer technique. REFERENCES 1. Gomeni R. Individual bioequivalence: Zeneca Pharma, 1 rue des

Chauffour, B.P. 127, 95022 Cergy, France.European Journal of pharmaceutical Sciences 1998; 6: S18. http://dx.doi.org/10.1016/S0928-0987(98)91271-4

2. WHO. Annex 7 Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. WHO Technical Report Series, No 2006; 937: 347–390.

3. FDA. Guidance for industry population pharmacokinetics; 1999. p. 1–35.

4. FDA. Guidance for industry bioavailability and bioequivalence studies for orally administered drug products – general considerations; 2003. p. 1–26.

5. HC. Guidance for industry preparation of veterinary abbreviated new drug submissions – generic drugs; 2010. p. 1–71.

6. FDA. Bioequivalence guidance; 2006. p. 1–28. 7. Wu CY, Benet LZ. Predicting drug disposition via application of BCS:

transport/ absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharmaceutical Research 2005; 22: 11–23. http://dx.doi.org/10.1007/s11095-004-9004-4

8. Abraham J, Lewis G. Harmonising and competing for medicines regulation: how healthy are the 0 2European Unions' systems of drug approval? Soc. Sci. Med 1999; 48: 1655-1667. http://dx.doi.org/ 10.1016/S0277-9536(99)00042-8

9. Stegman S, Leveiller F, Franchi D, Jong H. de, Linden H. When poor solubility becomes an issue: from early stage to proof of concept. Eur. J. Pharm. Sci 2007; 31: 249–261. http://dx.doi.org/10.1016/ j.ejps.2007.05.110 PMid:17616376

10. Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res 1995; 12: 413– 420. http://dx.doi.org/10.1023/A:1016212804288 PMid:7617530

11. Porter JH, Charman WN. In vitro assessment of oral lipid based formulations. Adv. Drug Deliv. Rev 2001; 50: 127–147. http://dx.doi. org/10.1016/S0169-409X(01)00182-X

12. Galia E Nicolaides E, Hörter D, Löbenberg R, Reppas C, Dressman JB. Evaluation of various dissolution media for predicting in vivo performance of class I and class II drugs. Pharm. Res 1998; 15: 698–705. http://dx.doi.org/10.1023/A:1011910801212 PMid:9619777

13. Nicolaides E, Symillides M, Dressman JB, Reppas C. Biorelevant dissolution testing to predict the plasma profile of lipophilic drugs after oral administration. Pharm. Res 2001; 18: 380–388. http://dx. doi.org/10.1023/A:1011071401306 PMid:11442280

14. Sunesen VH, Pedersen BL, Kristensen HG, Müllertz A. In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow through dissolution method with biorelevant dissolution media. Eur. J. Pharm. Sci 2005; 24: 305–313. http://dx.doi.org/10.1016/j.ejps.2004.11.007 PMid:15734297

15. Ettmayer P, Amidon GL, Clement B, Testa B. Lessons learned from marketed and investigational prodrugs. J Med Chem 2004; 47: 2393-2404. http://dx.doi.org/10.1021/jm0303812 PMid:15115379

16. Fahr A, Liu X. Drug delivery strategies for poorly water-soluble drugs. Expert Opin Drug Deliv 2007; 4: 403-416. http://dx.doi.org /10.1517/17425247.4.4.403 PMid:17683253

17. Gomez Orellana I. Strategies to improve oral drug bioavailability. Expert Opin Drug Deliv 2005; 2: 419-433. http://dx.doi.org/10.1517/ 17425247.2.3.419 PMid:16296764

18. Takagi T, Ramachandran C, Bermejo M, Yamashita S, Yu LX, Amidon GL. A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan. Molecular Pharmaceutics 2006; 3: 631–643. http://dx.doi.org/ 10.1021/mp0600182 PMid:17140251

19. Rege BD, Yu LX, Hussain AS, and Polli JE. Effect of common excipients on Caco-2 transport of low-permeability drugs. J. Pharm. Sci

2001; 90: 1776–1786. http://dx.doi.org/10.1002/jps.1127 PMid:1174 5735

20. Castro G. Intestinal physiology in parasitized host: Integration, disintegration, and reconstruction systems published in Neuro- Immuno physiology of the gastrointestinal mucosa. Implicationsfor inflammatory diseases. Ann. N.Y. Acad. Sci 1992; 664: 1–464. http://dx.doi.org /10.1111/j.1749-6632.1992.tb39775.x

21. Cesaro A, Russo E, and Crescenzi V. Kirkwood-Buff integrals and density fluctuations in aqueous solution of caffeine. J. Phys. Chem 1979; 80: 335. http://dx.doi.org/10.1021/j100544a026

22. Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. Journal of Pharmacological and Toxicological Methods 2000; 44: 235–249. http://dx.doi.org/10.1016/S1056-8719(00)00107-6

23. Lipinski CA. Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 2001; 46: 3–26. http://dx.doi.org/10.1016/S0169-409X(00)00129-0

24. Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomedicine and Pharmacotherapy 2004; 58: 173–182. http://dx.doi.org/10.1016/ j.biopha.2004.02.001 PMid:15082340

25. Kohli K, Chopra S, Dhar D, Arora S, Khar RK. Self-emulsifying drug delivery systems: an approach to enhance oral bioavailability. Drug Discovery Today 2010; 15: 958–965. http://dx.doi.org/10.1016 /j.drudis.2010.08.007 PMid:20727418

26. Mueller EA, Kovarik JM, van Bree JB, Tetzloff W, Grevel J, Kutz K. Improved dose linearity of cyclosporine pharmacokinetics from a microemulsion formulation. Pharmaceutical Research 1994; 11: 301–304. http://dx.doi.org/10.1023/A:1018923912135 PMid:8165192

27. Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems. Journal of Pharmaceutical Sciences 1971; 60: 1281–1302. http://dx.doi.org/10.1002/jps.2600600902

28. Vasconcelos T, Sarmento B, Costa P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discovery Today 2007; 12: 1068–1075. http://dx.doi.org/10.1016/ j.drudis.2007.09.005 PMid:18061887

29. Vaughn JM, Mc Conville JT, Crisp MT, Johnston KP, Williams 3rd, RO. Supersaturation produces high bioavailability of amorphous danazol particles formed by evaporative precipitation into aqueous solution and spray freezing into liquid technologies. Drug Development and Industrial Pharmacy 2006; 32: 559–567. http://dx.doi.org /10.1080/03639040500529176 PMid:16720411

30. Yamashita K, Nakate T, Okimoto K, Ohike A, Tokunaga Y, Ibuki R, Higaki K, Kimura T. Establishment of new preparation method for solid dispersion formulation of tacrolimus. International Journal of Pharmaceutics 2003; 267: 79–91. http://dx.doi.org/10.1016/j.ijpharm. 2003.07.010 PMid:14602386

31. Zerrouk N, Chemtob C, Arnaud P, Toscani S, Dugue J. In vitro and in vivo evaluation of carbamazepine-PEG 6000 solid dispersions. International Journal of Pharmaceutics 2001; 225: 49–62. http://dx. doi.org/10.1016/S0378-5173(01)00741-4

32. Zheng X, Yang R, Zhang Y, Wang Z, Tang X, Zheng L. Part II: bioavailability in beagle dogs of nimodipine solid dispersions prepared by hot-melt extrusion. Drug Development and Industrial Pharmacy 2007; 33: 783–789. http://dx.doi.org/10.1080/03639040601050205 PMid:17654027

33. Kushida I, Ichikawa M, Asakawa N. Improvement of dissolution and oral absorption of ER-34122, a poorly water-soluble dual 5- lipoxygenase/cyclooxygenase inhibitor with anti-inflammatory activity by preparing solid dispersion. Journal of Pharmaceutical Sciences 2002; 91: 258–266. http://dx.doi.org/10.1002/jps.10020 PMid:11782915

34. Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins. 1: Drug solubilization and stabilization. Journal of Pharmaceutical Sciences 1996; 85: 1017–1025. http://dx.doi.org/10.1021/js950534b PMid:8897265

35. Rajewski RA, Stella VJ. Pharmaceutical applications of cyclodextrins. 2: In vivo drug delivery. Journal of Pharmaceutical Sciences 1996; 85: 1142–1169. http://dx.doi.org/10.1021/js960075u PMid:8923319

36. Brewster ME, Loftsson T. Cyclodextrins as pharmaceutical solubilizers. Advanced Drug Delivery Reviews 2007; 59: 645–666. http://dx.doi.org/ 10.1016/j.addr.2007.05.012 PMid:17601630

37. Stephenson GA, Aburub A, Woods TA. Physical stability of salts of weak bases in the solid-state. Journal of Pharmaceutical Sciences 2011; 100: 1607–1617. http://dx.doi.org/10.1002/jps.22405 PMid:21374599

38. Badawy SI, Hussain MA. Microenvironmental pH modulation in solid dosage forms. Journal of Pharmaceutical Sciences 2007; 96: 948–959. http://dx.doi.org/10.1002/jps.20932 PMid:17455349

39. Kranz H, Guthmann C, Wagner T, Lipp R, Reinhard J. Development of a single unit extended release formulation for ZK 811 752, a weakly


JPSI 2 (6), Nov-Dec 2013, 10-16

basic drug. European Journal of Pharmaceutical Sciences 2005; 26: 47–53. http://dx.doi.org/10.1016/j.ejps.2005.04.018 PMid:15953712

40. Badawy SI, Gray DB, Zhao F, Sun D, chuster AE, Hussain MA. Formulation of solid dosage forms to overcome gastric pH interaction of the factor Xa inhibitor, BMS-561389. Pharmaceutical Research 2006; 23: 989–996. http://dx.doi.org/10.1007/s11095-006-9899-z PMid:167 15389

41. Horter D, Dressman JB. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Advanced Drug Delivery Reviews 2001; 46: 75–87. PMid:11259834

42. Mosharraf M, Nyström C. The effect of particle size and shape on the surface specific dissolution rate of microsized practically insoluble drugs. International Journal of Pharmaceutics 1995; 122: 35–47. http://dx.doi.org/10.1016/0378-5173(95)00033-F

43. Atkinson RM, Bedford C, Child KJ, Tomich EG. Effect of particle size on blood griseofulvin-levels in man. Nature 1962; 193: 588–589. http://dx.doi.org/10.1038/193588a0 PMid:13863116

44. Müller RH, Peters K. Nanosuspensions for the formulation of poorly soluble drugs: I. Preparation by a size-reduction technique. International Journal of Pharmaceutics 1998; 160: 229–237. http://dx.doi.org /10.1016/S0378-5173(97)00311-6

45. Shegokar R, Muller RH. Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. International Journal of Pharmaceutics 2010; 399: 129–139. http://dx.doi.org/10.1016/j.ijpharm.2010.07.044 PMid:20674732

46. Fakes MG, Vakkalagadda BJ, Qian F, Desikan S, Gandhi RB, Lai C, Hsie A, Franchini MK, Toale H, Brown J. Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amorphous formulation approaches. International Journal of Pharmaceutics 2009; 370: 167–174. http://dx.doi.org/10.1016 /j.ijpharm.2008.11.018 PMid:19100319

47. Kapoor A, Majumdar DK, Yadav MR. Crystal forms of nimesulide– a sulfonanilide (non-steriodal anti inflammatory drug) Indian J Chem 1998; 37B: 572–575.

48. Burt HM, Mitchell AG. Effect of habit modification on dissolution rate Int. J Pharm 1980; 5: 239–251. http://dx.doi.org/10.1016/0378-5173( 80)90131-3

49. Watanable A, Yamaoka Y, Takada K. Crystal habits and dissolution behavior of aspirin. Chem. Pharm Bull 1982; 30: 2958–2963. http://dx.doi.org/10.1248/cpb.30.2958

50. Chow AHL, Chow PKK, Wang Z, Grant DGW. Modification of acetaminophen crystals; influence of growth in aqueous solutions containing.p-aceto oxyacetanilibe on crystal properties. Int J Pharm 1985; 23: 239–258. http://dx.doi.org/10.1016/0378-5173(85)90024-9

51. Femi Oyewo MN, Spring MS. Studies on paracetamol crystals produced by growth in aqueous solutions. Int J Pharm 1994; 112: 17–28. http:// dx.doi.org/10.1016/0378-5173(94)90257-7

52. Garekani HA, Ford JL, Rubinstein MH, Rajabi Siah Boomi AP. Highly compressible paracetamol; compression properties. Int J Pharm 2000; 208: 101–110. http://dx.doi.org/10.1016/S0378-5173(00)00551-2

53. Lahra M, Leiserowitz L. The effect of solvent on crystal growth and morphology. Chem Eng Sci 2001; 56: 2245–2253. http://dx.doi.org/ 10.1016/S0009-2509(00)00459-0

54. Rodriguez Spong B, Price CP, Jayasankar A, Matzger AJ, Rodriguez Hornedo N. General principles of pharmaceutical solid polymorphism: a supramolecular perspective. Advanced Drug Delivery Reviews 2004; 56: 241–274. http://dx.doi.org/10.1016/j.addr.2003.10.005 PMid:1496 2581

55. Blagden N, De Matas M, Gavan PT, York P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Advanced Drug Delivery Reviews 2007; 59: 617–630. http://dx.doi.org/10.1016/j.addr.2007.05.011 PMid:17597252

56. Pudipeddi, M, Serajuddin AT. Trends in solubility of polymorphs. Journal of Pharmaceutical Sciences 2005; 94: 929–939. http://dx. doi.org/10.1002/jps.20302 PMid:15770643

57. Zhang GG, Law D, Schmitt EA, Qiu Y. Phase transformation considerations during process development and manufacture of solid oral dosage forms. Advanced Drug Delivery Reviews 2004; 56: 371–390. http://dx.doi.org/10.1016/j.addr.2003.10.009 PMid:14962587

58. Childs SL, Stahly GP, Park A. The salt-cocrystal continuum: the influence of crystal structure on ionization state. Molecular Pharmaceutics 2007; 4: 323–338. http://dx.doi.org/10.1021/mp0601345 PMid:17461597

59. Serajuddin AT. Salt formation to improve drug solubility. Advanced Drug Delivery Reviews 2007; 59: 603–616. http://dx.doi.org/ 10.1016/j.addr.2007.05.010 PMid:17619064

60. Avdeef A. Solubility of sparingly-soluble ionizable drugs. Advanced Drug Delivery Reviews 2007; 59: 568–590. http://dx.doi.org/10.1016 /j.addr.2007.05.008 PMid:17644216

61. Guzman HR, Tawa M, Zhang Z, Ratanabanangkoon P, Shaw P, Gardner CR, Chen H, Moreau JP, Almarsson O, Remenar JF. Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations. Journal of Pharmaceutical Sciences 2007; 96: 2686–2702. http://dx.doi.org /10.1002/jps.20906 PMid:17518357

62. Li S, Wong S, Sethia S, Almoazen H, Joshi YM, Serajuddin AT. Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH. Pharmaceutical Research 2005; 22: 628–635. http://dx.doi.org/10.1007/s11095-005-2504-z PMid:15 846471

63. Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Crystal Growth Design 2009; 9: 2950–2967. http://dx.doi.org/10.1021/cg900129f PMid:19503732 PMCid:PM C2690398

64. Jung MS, Kim JS, Kim MS, Alhalaweh A, Cho W, Hwang SJ, Velaga SP. Bioavailability of indomethacin-saccharin cocrystals. The Journal of Pharmacy and Pharmacology 2010; 62: 1560–1568. http://dx. doi.org/10.1111/j.2042-7158.2010.01189.x PMid:21039541

65. Bak A, Gore A, Yanez E, Stanton M, Tufekcic S, Syed R, Akrami A, Rose M, Surapaneni S, Bostick T, King A, Neervannan S, Ostovic D, Koparkar A. The co-crystal approach to improve the exposure of a water-insoluble compound: AMG 517 sorbic acid co-crystal characterization and pharmacokinetics. Journal of Pharmaceutical Sciences 2008; 97: 3942–3956. http://dx.doi.org/10.1002/jps.21280 PMid:18214948

How to cite this article: Ajay D. Kshirsagar, Omkar N. Shikare, Haidarali M. Shaikh. Bioavailability and bioequivalence study in correlation of biopharmaceutics classification system (BCS) and possible modification. J Pharm Sci Innov. 2013; 2(6): 10-16.

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