Solid Forms and Pharmacokinetics

Piramal Life Sciences Limited, 1, Nirlon Complex, Goreagon (East), Mumbai, 400 063, India 

Together they are popularly known as the ADMET properties of a drug and determine the distribution of the drug both temporally and spatially in the body. 

Structural Physicochemical Biochemical Pharmacokinetic Molecular weight, ionization, polarity, lipophilicity/hydrophilicity, shape, reactivity, polar surface area, H-bonding Solubility, dissolution rate, permeability, chemical stability Protein/tissue/cell binding, metabolism, receptor mediated transport (influx and efflux) Bioavailability, half-life, clearance, drug-drug interactions, toxicity, maximum concentrations in plasma 

The dissolution of a drug is a function of the pH of the environment it is exposed to and the pK of the molecule. It is facilitated by the pH gradient in the GI tract as predicted by the Henderson-Hasselbalch equation (equation (7.1)). For instance, basic drugs ionize in the acidic pH of the stomach and the upper parts of the intestine while acidic drugs remain neutral and have very 

Solubility of the lipophilic molecules, does not however, gain from the pH gradient of the GI tract. Their solubility is aided by the bile acids secreted from the gallbladder into the intestinal region. 

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As this book makes it clear, the study of pharmaceutical co-crystals opens up new opportunities for the pharmaceutical industry. Several chapters of this book have addressed essential aspects, such as the role of co-crystals in the pharmaceutical development continuum (N. Schultheiss and J.-O. Henck), solid forms and pharmacokinetics (N. Biswas), the process of co-crystallization and scale up issues (E. Gagniere, D. Mangin, S. Veesler and F. Fuel), solid state analytical techniques and strategies for characterization (S. Reutzel-Edens) as well as opportunities and pitfalls when embarking on co-crystal search for broadening IP rights (M. Hoffmann and J. Lindeman). 

The present revised textbook on Pharmaceutical Drug Analysis caters for the much needed handbook and reference book, which is absolutely current with regard to the esteemed philosophy of analytical chemistry, an obvious solid support towards drug discovery, development, stability studies, bioavailability and pharmacokinetic studies, and above all the quality assurance of pure drugs together with their respective dosage forms. 

All of the examples discussed in Section 7.2.3, reveal the great potential of solid forms that can be exploited to achieve the desired pharmacokinetic properties. However, one has to also keep in mind the possibility that an increase in dissolution rate and solubility could sometimes even prove to be detrimental. It could lead to the accumulation of the drug, beyond the equilibrium solubility, creating a driving force for the nucleation and crystallization of some stable phases in the physiological medium. To avoid any such accumulation, the drug should possess a sufficient absorption rate for its optimal distribution in the body. 

There are numerous accounts in the literature of increased bioavailability in animals when changing the solid state. Kato and Kohetsu (1981) showed that form II amobarbital is more rapidly absorbedn vivo than form I. Dissolution rate experiments in water at(3"Showed a 1.6 times faster dissolution ratei vitro for form II compared to form I. Yokoyama et al. (1981) found that form III of 6-mercaptopurine was 1.5 times as bioavailable in rabbits as form I. It was six to seven times as soluble as the form I polymorph in studies by Kuroda et al. (1982). Kokubu et al. (1987) examined the therapeutic effect of different polymorphs of cimetidine in inhibition of ulcers in the rat. Pharmacokinetic studies found that form C was 1.4-1.5 times as bioavailable as forms A and B. This translated into a greater protection against stress ulceration, as shown in Table 19.4. The effec of form C was signiLcant compared to forms A, B, and D, which were all equivalent. 

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