SC I B. Polymorphism

1. Polymorphism (the occurrence of more than one morphic form) is a function of the internal structure of crystalline solids. Its occurrence cannot be predicted and, as it can be induced in many materials in appropriate conditions, its absence is difficult to demonstrate using a single, specific test. Different polymorphs may exhibit different physicochemical properties such as melting point, dissolution rate and infrared absorption spectrum. In some cases these may affect the handling characteristics of the material, the stability of formulated preparations and bioavailability. Control of morphic form by a manufacturer is necessary during processing of active ingredients and excipients and during production of a formulated product to ensure the correct physical characteristics of the product. Its main importance to the control of medicinal products is in the areas of bioavailability and stability.

2. The morphic form of a readily soluble starting material that is incorporated into a solution, for example, an injection, an oral solution or eye drops, is not usually important. (An exception to this statement might be if the concentration of the solution is such that it is close to the limit of solubility of one of the possible polymorphs.) The morphic form may be important when the material is included in a solid dosage form or as a suspension in a liquid dosage form when the characteristics of the different polymorphs are such as to affect the bioavailability of the material.

3. Pharmaceutical and medicinal substances For most substances it will not usually be appropriate or necessary for the monograph to control the morphic form. There are, however, a few monographs that restrict the substance to a single form. This may be done by permitting no deviation from the spectrum/form of the reference substance prescribed or by restricting the melting point range. An example is Carbamazepine where the infrared spectrum is determined without prior treatment of the sample and the melting range permitted excludes the polymorph of lower melting point.

4. Where it is known that the substance exists in more than one morphic form a statement is frequently included in the monographs of the Pharmacopoeia under Characteristics, for example, the monographs for Dextropropoxyphene Napsilate and Spironolactone. In the absence of such a statement, the existence of polymorphism may sometimes be deduced from the tests of the monograph. The most common example is found in infrared identification tests where the analyst may be instructed to prepare a solution spectrum or recrystallise the sample if the spectrum obtained is not concordant with the reference spectrum or spectrum of a reference substance, for example, Prednisolone Sodium Phosphate. This procedure recognises polymorphism but does not limit the form permitted.

5. It is intended to extend the inclusion of explicit statements in monographs for pharmaceutical and medicinal substances as information on the occurrence of polymorphism becomes available. The Commission would welcome information from users of the Pharmacopoeia in order that such statements can be added in appropriate cases.

6. Formulated preparations Polymorphism is a potential problem in solid dosage forms, such as tablets, or in liquid or semi-solid preparations where the active ingredient is present as a solid, for example, in oral suspensions. In most cases it is difficult to demonstrate that the material contains the desired polymorph as the process of extracting a sufficient sample of the material in question for analysis may itself change the form of the material. For a solid dosage form where the active ingredient is known to exist in forms with significant differences in solubility, a dissolution test may be the method of choice.

7. Where the active ingredient is known to exist in more than one morphic form and the choice of polymorph is critical with regard to bioavailability and/or stability, the method of manufacture should ensure the presence of the correct amount of the desired polymorph in the preparation. In future the side heading ‘Production’ will be used to draw attention to control of morphic form during manufacture in cases where control of morphic form is known to be important.

8. Such Production statements might also include reference to the need during product development to examine drug sensitivity to polymorphic change due to granulation conditions or compressional forces and to make appropriate processing adjustments to control potential variation.

9. The Commission would find it helpful to be advised of instances where control of morphic form is important so that a suitable Production statement may be added. In such cases it would also appreciate receiving details of any validated test methods that will appropriately limit the undesirable form.