Polymorphic Crystal Forms and Cocrystals in Drug Delivery (Crystal Engineering)

Abstract

Active pharmaceutical ingredients, APIs, are most conveniently developed and delivered orally as solid dosage forms that contain a defined crystalline form of an API. This means that the pharmacokinetic profile of a dosage form is at the very least linked to the physicochemical properties of the crystal form that is selected for development. Furthermore, that crystal forms of new chemical entities are novel, lack obviousness, and have utility makes them patentable. Therefore, selection of a specific crystal form for a given API is a profoundly important step in drug development from clinical, legal, and regulatory perspectives. In this context, scientific developments that afford greater understanding of and diversity in the number of crystalline forms available for a given API, which have traditionally been limited to salts, polymorphs, and hydrates/solvates [(a) Byrn SR, Pfeiffer RR, Stowell JG. Solid State Chemistry of Drugs. 2nd ed. West Lafayette, IN: SSCI, Inc.; 1999. (b) Haleblian JK. J. Pharm. Sci. 1975;64:1269–1288.], are obviously of relevance to the pharmaceutical industry. The science of crystal engineering [(a) Etter MC. J Phys Chem 1991;95:4601–4610. (b) Zerkowski JA, MacDonald JC, Seto CT, Wierda DA, Whitesides GM. J Am Chem Soc 1994;116:2382–2391. (c) Pepinsky R. Phys Rev 1955;100:971. (d) Schmidt GMJ. Pure Appl Chem 1971;27:647–678. (e) Desiraju GR. Crystal Engineering: The Design of Organic Solids. Amsterdam: Elsevier; 1989. (f) Moulton B, Zaworotko MJ. Chem Rev 2001;101: 1629–1658. (g) Braga D. Chem Commun 2003;22:2751–2754. (h) Hosseini MW. Coord Chem Rev 2003;240:157–166. (i) Desiraju GR. Angew Chem Int Ed Engl 1995;34: 2311–2327.] focuses upon self‐assembly of existing molecules or ions and it has evolved in such a manner that a wide range of new crystal forms can be generated without the need to invoke covalent‐bond breakage or formation. This contribution will address the impact of crystal engineering upon our fundamental understanding of crystal form diversity and how physical properties of crystals can be customized via the emerging class of crystal forms that have been termed pharmaceutical cocrystals [(a) Almarsson Ö, Zaworotko MJ. Chem Commun 2004; 1889–1896. (b) Vishweshwar P, McMahon JA, Bis JA, Zaworotko MJ. J Pharm Sci 2006;95:499–516. (c) Peterson ML, Hickey MB, Zaworotko MJ, Almarsson O. J Pharm Pharm Sci 2006;9:317–326. (d) Zaworotko M. Am Pharm Outsourc 2004;5: 16–23. (e) Shan N, Zaworotko MJ. Drug Discov Today 2008;13:440–446. (f) Blagden N, de Matas M, Gavan PT, Yoark P, Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates Adv Drug Del Rev 2007;59:617–630. (g) Nangia A. Cryst Growth Des 2008;8:1079–1081].

Changes in the Solid State of Nicergoline, a Poorly Soluble Drug, Under Different Grinding and Environmental Conditions: Effect on Polymorphism and Dissolution

“…The hydrate showed the worst IDR, in line with Khankari and Grant 29 , who reported that the solubility and thus the dissolution rates of hydrates are worse than those of the parent forms [29][30][31] .…”

Coformer Selection in Pharmaceutical Cocrystal Development: a Case Study of a Meloxicam Aspirin Cocrystal That Exhibits Enhanced Solubility and Pharmacokinetics

“…A recent review of the scientific and patent literature indicated that there have been at least 10 pharmaceutical cocrystal case studies with PK details reported to date, many of which support that pharmaceutical cocrystals are a viable option to enhance the clinical performance of a poorly soluble API. 17,18 Clearly, pharmaceutical cocrystals represent an opportunity to diversify the number of crystal forms of a given API and in turn fine tune or even customize its physicochemical and PK properties without the formation/breakage of covalent bonds.…”

Preparation and Solid-State Characterization of Three Novel Multicomponent Solid Forms of Oxcarbazepine: Improvement in Solubility through Saccharin Cocrystal

“…Pharmaceutical cocrystals are also capable of modifying pharmacokinetic (PK) properties. A recent review has summarized the case studies where the effect of cocrystals on the PK profile has been evaluated, many of which support that pharmaceutical cocrystals are a viable option to enhance the clinical performance of a poorly soluble API. − Hickey et al reported a pharmacokinetic study on cocrystals and a marketed form (Tergretol) of carbamazepine in dogs which revealed that the cocrystal showed higher plasma levels than Tergretol which contained an anhydrous polymorph of carbamazepine. According to a more recent report by Zaworotko et al, a cocrystal of meloxicam and aspirin was prepared, which enabled an approximately 12-fold decrease in the time required to reach a concentration of 0.51 g/mL in rats compared with pure meloxicam at an equivalent dose.…”