Physical stability polymorphism

Studies of polymorphs in recent years have pointed out the effects of polymorphism on solubility and, more specifically, on dissolution rates. The aspect of polymorphism that is of particular concern to the parenteral formulator is physical stability of the product [8]. Substances that form polymorphs must be evaluated so that the form used is stable in a particular solvent system. Physical stresses that occur during suspension manufacture may also give rise to changes in crystal form [9]. 

The chemical and physical stability of aqueous and nonaqueous suspensions of a number of solvatomorphs of niclosamide has been evaluated in an effort to develop pharmaceutically acceptable suspension formulations [90]. Studied in this work was the anhydrate, two polymorphic monohydrates, the 1 1, Y, A"-dimethyI I ormam ide solvatomorph, the 1 1 dimethyl sulfoxide solvatomorph, the 1 1 methanol solvato-morph, and the 2 1 tetraethylene glycol hemisolvate. All of the solvatomorphs were found to convert initially to one of the polymorphic monohydrates, and over time converted to the more stable monohydrate phase. The various solvatomorphs could be readily desolvated into isomorphic desolvates, but these were unstable and became re-hydrated or re-solvated upon exposure to the appropriate solvent. 

Polymorphism is critically important in the design of new drug API [9] and affects a number of areas. The main impact is to the bioavailability and release profile of a drug substance into the body. This is due to differences in solubility and dissolution rate, between the polymorphs. The chemical and physical stability of the formulated drug substance is also dependent on the polymorphic form. Patented registration of all discovered forms and their manufacturing conditions is an important element in protecting a pharmaceutical companies intellectual property. 

The magnitudes of the solubility of forms I and II of this drug varied signiLcantly in water, decyl alcohol, and dodecyl alcohol. However, their data showed that the solubility ratio was independent of solvent, but dependent on temperature. Figure 19.3 shows the data for these polymorphs in water The difference in slopes (indicating a difference in enthalpies of fusion) for the two polymorphs can be used to calculate a transition temperature, where both forms have the same physical stability The identity of the metastable form and the degree of solubility enhancement both depend on the temperature chosen for comparison. 

Physical stability of the active ingredient is an important factor that should not be overlooked. The effect of polymorphism on properties of both the active ingredient (e.g., chemical stability, solubility, dissolution rate) and the drug product (e.g., bioavailability) have been extensively studied. Polymorphs or amorphous states of the active ingredient may impact chemical stability as well as dissolution rates, solubility, and bioavailability. This should be studied appropriately. This is discussed further in the sections below. 

Physical stability, the propensity of compounds to adopt different polymorphs depending on methods of isolation is also now beginning to be tackled by the computational chemist. Ideally, molecules which can only crystallise as a single polymorph would be preferred, although preparation of a compound in the desired (most stable) polymorph, can usually be mastered by the experimental chemist. Nonetheless, identification of the 50% of organic molecules likely to crystallise in different polymorphs would be useful, especially if this can be predicted from the molecular structure of the compounds even before they are synthesised. 

There are some useful methods to improve the physical stability of a suspension, such as decreasing the salt concentration, addition of additives to regulate the osmolarity, as well as changes in excipient concentrations, unit operations in the process, origin and synthesis of the drug substance, polymorphic behavior of the drug substance crystals, and other particle characteristics. However, methods based on changes of the particle properties and the surfactants used are the most successful [43],... 

Polymorphs are crystalline compounds of the same molecular structure that have a different arrangement of molecules in the unit cell. Polymorphs have the same chemical composition but have unique cell parameters. Therefore, polymorphs can have very different melting temperatures, densities, solubilities, chemical and physical stabilities, dissolution rates, and bioavailabilities. ° ... 

Crowley, K.J. Zografi, G. Cryogenic grinding of indomethacin polymorphs and solvates assessment of amorphous phase formation and amorphous phase physical stability. J. Pharm. Sci. 2002, 91, 492-507. 

Wet massing Wet granulation Polymorphic conversion hydrate formation salt to free aetd/base conversion amorphous phase formation Chemical and physical stability dissolution rate... 

Physical Stability Physical stability can refer to molecular level changes, such as polymorphic changes, or macroscopic changes, such as dissolution rate or... 

When improvements in the physical stability of a product are needed, choices must be based upon the nature of the problem and the desired goal. One of the first choices made is to use the most stable polymorph of the drug. This may involve an extensive polymorph screening effort to attempt to find the most stable polymorph. If the most stable polymorph is undesirable for some reason (e.g., solubility issues), then avoiding contamination of the desired polymorph with seeds of the most stable polymorph becomes very important. In a product that uses an amorphous form of a drug, it is critical to inhibit crystallization to avoid dramatic changes in stability and solubility. 

For the very first clinical studies it is often possible to find a polymorph with sufficient physical stability to permit completion of Phase I trials. The most stable polymorph usually exhibits the highest density, the lowest solubility (and often the lowest bioavailability). Very detailed evaluations of polymorphism and the inter-relationships between the different polymorphs and pseudopolymorphs usually need to be delayed until the candidate salt has been chosen and larger quantities of drug from several batches are available. These studies are often started around the initiation of Phase 11 clinical trials. 

Stability) will eventually decrease. Similarly, if a metastable polymorph is used to formulate a suspension product, aggregation will be found on standing. However, if a stable polymorph with a low energy level is used, a stable suspension may result. The physical stability of a suspension may be determined by observing the column height of the suspension in a graduated cylinder. 

Some new drug substances exist in different crystalline forms that differ in their physical properties. Polymorphism may also include solvation or hydration products (also known as pseudopol5rmorphs) and amorphous forms. Differences in these forms could, in some cases, affect the quality or performance of the new drug products. In such cases, the bioavailabUity stability can be altered requiring choice of specific stable solid dosage forms. 

If the drug is insufficiently soluble to allow delivery of the required dose as a solution (the maximum delivered dose for each nostril is 200 p,L), then a suspension formulation will be required. There are additional issues for suspension products, for example crystal growth, physical stability, resuspension, homogeneity and dose uniformity. Suspension products will also require information on density, particle size distribution, particle morphology, solvates and hydrates, polymorphs, amorphous forms, moisture and/or residual solvent content and microbial quality (sterile filtration of the bulk liquid during manufacture is not feasible). 

Morphic state It must be clear whether the salt is monomorphic or polymorphic. If it is polymorphic, the relationship between the polymorphic forms (monotropic, enantiotropic), their relative thermodynamic stability (stable or metastable at room temperature) and the temperature range of their physical stability need to be clarified. 

Physical stability related to API polymorphic changes and API crystallization are generally limited by mobility. Since mobility effects generally follow an Arrhenius relation, such processes are often accelerated by elevated temperatures in a predictive manner however, there will often be a discontinuity at any phase change (such as a melt or glass transition). 

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