Crystalline drugs polymorphic forms

Bulk drug products often exist in different crystalline or polymorphic forms. Because the polymorphs of a specific API can exhibit dis-tinguishably different bulk stability properties as well as bioavailability characteristics as a result of the differences in surface area between the different crystalline forms, specification of the polymorphic form is recommended for FDA submission. Products such as ranitidine (10), lorazepam (11), and natamy-cin (12) serve as examples of APIs that exist in several different polymorphic forms. The solvent system and the crystallization conditions generally determine the specific crystallization form that is isolated. Polymorph selection for regulatory submission is usually based on the ability to reliably produce and process the material in the same crystalline form. In many cases this is the thermodynamically most stable polymorphic form. In the event that a less stable polymorphic form is desired, because of stability or bioavailability issues, seeding techniques can be used to control the crystallization selectivity of a specific polymorph. 

The dependence of solubility on the particular form of the solid involved has some important implications for drug discovery. An amorphous solid, often the result of lyophylization, crashing out , or evaporating chromatography fractions, for example, will be much more soluble than the same compound when crystalline. Even when crystalline, different polymorphic forms of the same compound will have different solubilities, with the most stable polymorph often being the last to form and the least soluble. Years ago, most research compounds were... 

Pharmacists should also take a dim view of changes in the particle size, size distribution, or particulate nature of semisolid suspensions. They are the consequence of crystal growth, changes in crystalline habit, or the reversion of the crystalline materials to a more stable polymorphic form. Any crystalline alteration can lead to a pronounced reduction in the drug-delivery capabilities and therapeutic utility of a formulation. Thus, products exhibiting such changes are seriously physically unstable and unusable. 

This chapter describes some of the properties of solids that affect transport across phases and membranes, with an emphasis on biological membranes. Four aspects are addressed. They include a comparison of crystalline and amorphous forms of the drug, transitions between phases, polymorphism, and hydration. With respect to transport, the major effect of each of these properties is on the apparent solubility, which then affects dissolution and consequently transport. There is often an opposite effect on the stability of the material. Generally, highly crystalline substances are more stable but have lower free energy, solubility, and dissolution characteristics than less crystalline substances. In some situations, this lower solubility and consequent dissolution rate will result in reduced bioavailability. 

Crystalline or amorphous forms of fhe drug substance can affect product efficacy. Polymorphic forms usually exhibif different physical-chemical properties, including melting point and solubility. The occurrence of polymorphic forms with drugs is relatively... 

It is essential to understand how and when the polymorphs of drug substance in oral liquid dosage forms and suspensions can be controlled. One approach to study this phenomenon is to seed the formulation with a small amount of a known polymorphic crystal (other than what is used for the product), which is a common practice to rapidly determine what effect this may have on long-term storage. From these types of studies, the appropriate excipients can be used to preserve the specific polymorphic form desired. However, even when the drug in its crystalline form is studied extensively, there are cases when a previously unknown polymorph may be formed in solution and lead to precipitation (14). 

The physical form of the salt must be taken into account and several issues must be considered (Serajuddin and Pudipeddi, 2002). Forexample, amorphous material might result. Even if crystalline, the salt form might prove to be polymorphic. On crystallization or recrystallization, formation of a hydrate or a solvate might occur, and the effect of temperature and humidity on this form should be investigated. Both the physical and chemical stability of the different candidate salt forms in the solid state will ultimately deLne the optimal form of the drug. 

The occurrence of multiple polymorphic forms of crystalline drugs and excipients is well known to pharmaceutical scientists, and the possible occurrence of polymorphic forms of amorphous pharmaceutical... 

We will consider two drugs that exhibit this phenomenon. Spironolactone (I), which is a diuretic steroidal aldosterone agonist, crystallises as two polymorphic forms and also as four solvated crystalline forms depending on the solvents and methods used for crystallisation. We will consider the occurrence of solvated forms in section 1.4 at the moment we will concentrate on the two polymorphs only. Form 1 is produced when spironolactone powder is dissolved in acetone at a temperature very close to the boiling point and the solution is then cooled within a few hours down to O C. Form 2 is produced when the powder is dissolved in acetone, dioxane or chloroform at room temperature and the solvent is allowed to spontaneously evaporate over a period of several weeks. In both polymorphs the steroid nuclei (A, B, C and D rings)... 

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