Drug polymorphism and dosage form design: a practical perspective
Introduction
The subject of drug polymorphism has received extensive academic and industrial attention since the early pioneering reports of Aguiar and colleagues at Parke-Davis, in which effects of polymorphism on dissolution and bioavailability were highlighted for chloramphenicol palmitate [1], [2]. Drug polymorphism has been the subject of hundreds of publications and numerous excellent reviews. For both an overview and an in-depth analysis of this complex field, see the excellent series of reviews in Volume 48 (2001) of Advanced Drug Delivery Reviews [4], [5], [6], [7], [8], [9], in “Polymorphism in Pharmaceutical Sciences” edited by Brittain [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], and in “Solid State Chemistry of Drugs” by Byrn et al. [20]. In addition, two very clear reviews/commentaries from the regulatory perspective have appeared [21], [22].
At this point in time, it would be difficult to say anything novel about the effects of polymorphism on physical stability, chemical stability, manufacturability, or oral absorption that has not been reviewed in the references quoted above. In many respects, the 1969 review by Haleblian and McCrone was prescient in its broad coverage of the issues of polymorphism in pharmaceuticals [23]. In this article, we make no effort to review once again the vast literature on drug polymorphism. Furthermore, we do not here discuss theoretical or experimental details of the study of polymorphism. Rather, we attempt to provide a practical perspective on the impact of polymorphism on chemical stability, manufacturability, and bioavailability, with particular attention to a limited number of illustrative cases from our experience and the literature. Such a practical perspective must involve generalizations for which there are occasional exceptions.
Section snippets
Why develop multiple polymorphs?
It is generally accepted that, during the course of development of a drug, the lowest energy crystalline polymorph should be identified and chosen for development. This is critically important because the post-approval appearance of a polymorph with lower energy than the marketed polymorph can be catastrophic, as happened with the HIV protease inhibitor ritonavir [24]. For this reason, innovator pharmaceutical companies expend significant resources on this technical issue early in the
Chemical stability of polymorphs and amorphous forms
The polymorphs (or pseudopolymorphs) of some drugs have been shown to exhibit different chemical stability. Examples are carbamezepine [25], paroxetine maleate [26], indomethacin [27], methyprednisolone [28], furosemide [29], and enalapril maleate [30]. For example, the photodecay of form II of carbamezepine was 5- and 1.5-fold faster than forms I and III, respectively [25]. In addition to a change in the rate of decay, polymorphism may also affect the mechanism of decay, as observed in the
Mechanical properties of polymorphs and amorphous drug forms
Polymorphism can affect the mechanical properties of drug particles, and thus may impact the manufacturability and physical attributes of tablets. For example, polymorphs of metoprolol tartrate [46], paracetamol [47], [48], [49], [50], sulfamerazine [51], phenobarbitone [52], carbamazepine [53], [54], phenylbutazone [55] and other drugs have been shown to exhibit different mechanical properties. A common effect of polymorphism is alteration of powder flow due to the difference in particle
Bioavailability of polymorphs
There are many reports of polymorph-dependent bioavailability and/or absorption rate, with much of this work done in animals. See for example animal studies of chloramphenicol palmitate [59], phenylbutazone [60], amobarbitol [61], cimetidine [62], 6-mercaptopurine [63], and chlortetracycline [64]. For the purpose of the present analysis, we consider only human studies in detail.
Metastable crystalline polymorph versus amorphous form
As discussed above, metastable crystalline polymorphs and amorphous forms may be less chemically stable and potentially possess different (in some cases less desirable) mechanical properties than the related stable crystalline form. These potential problems can in theory be solved by judicious choice of excipients and appropriate formulation strategies. In addition to chemical instability and mechanical properties, physical stability of the drug during product shelf life is of paramount
Conclusions
In principle, any polymorph or hydrate/solvate or amorphous form of a drug can be appropriately formulated. In practice, for some drugs constraints may be encountered. In general, the following conclusions are drawn from the literature and the experience of the authors:
- 1.
It is always advisable to identify the lowest energy crystalline polymorph of a drug candidate during development, and to develop this form. While this form may not be the most processable form available, processing deficits can
Acknowledgements
We thank Ravi Shanker and Bruno Hancock of Pfizer for very helpful reviews of our manuscript. We also thank Andre Raw of FDA and the anonymous reviewers for comments which helped us communicate our practical perspective with more clarity.
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