Polymorphic forms, solubility

Fig. 5 Dissolution profiles obtained from the solubility determination of two polymorphic forms of the same drug substance. A is the stable form with solubility 31 mg/mL. B is the profile of the metastable form with solubility 46 mg/mL. This solubility (circles) is not achieved in many instances, and precipitation of the stable form occurs at a point beyond the solubility of A, and the trace becomes B. C is the hypothetical profile of the metastable form. 

Knowledge of polymorphic forms is of importance in preformulation because suspension systems should never be made with a metastable form (i.e., a form other than the stable crystal form). Conversely, a metastable form is more soluble than a stable modification, and this can be of advantage in dissolution [Eq. (9)]. There are two types of polymorphism, a fact illustrated in the following discussion. 

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]. 

A polymorph is a solid crystalline phase of a compound resulting from the possibility of at least two different crystal lattice arrangements of that compound in the solid state [42], Polymorphs of a compound are, however, identical in the liquid and vapor states. They usually melt at different temperatures but give melts of identical composition. Two polymorphs of a compound may be as different in structure and properties as crystals of two different compounds [43,44], Apparent solubility, melting point, density, hardness, crystal shape, optical and electrical properties, vapor pressure, etc. may all vary with the polymorphic form. The polymorphs that are produced depend upon factors such as storage temperature, recrystallization solvent, and rate of cooling. Table 2 suggests the importance of polymorphism in the field of pharmaceutics [45],... 

Let us now take a closer look at the theory relating polymorphism and solubility [46], Consider a drug that has two polymorphic forms, polymorph 1 and polymorph 2. If the subscripts 1 and 2 refer to the respective polymorphs, we can state their free energies as... 

At a certain temperature of transition Tt, the two forms will be in equilibrium, AG will be zero, and m = m2. But at other temperatures the two forms will not be in equilibrium, and if ax > a2 then because AG = Z rin (a2/fli), AG will be negative and polymorph 1 will change spontaneously to polymorph 2 and will therefore be considered the less stable form and vice versa. Studies of the two polymorphic forms of methylprednisolone show that significant differences occur in the apparent solubilities of polymorphic forms and that these may be temperature-related. 

As previously discussed, compound form differs markedly between early discovery and the late discovery/development interface. The early discovery compound is poorly characterized as to its crystalline form - it may be nonsolid, amorphous, or possibly crystalline but uncharacterized as to polymorphic form. The late discovery/development interface compound is crystalline as defined by phase-contract microscopy or powder X-ray diffraction, and its polymorphic and salt form is frequently characterized. This difference has profound implications for the design of a discovery solubility assay. The key question is this Is it better to design an early discovery solubility assay as a separate type of experiment, or is it better to try to automate a traditional thermodynamic solubility assay to handle the very large number of compounds likely to be encountered in early discovery Another way to state this question is this Does it make sense to run a thermodynamic solubility assay on poorly crystalline early discovery compounds This is the type of question about which reasonable people could disagree. However, this author does have a distinct opinion. It is much better to set up a distinctively different solubility assay in early discovery and to maintain a clear distinction between the assay type appropriate in early discovery and the assay type appropriate at the late discovery/ development interface. Two issues are relevant to this opinion One relates to the need for a solubility assay to reflect/predict early discovery stage oral absorption and the other relates to people/chemistry issues. 

It is well known that many compounds are able to change their physical form whilst suspended in solution. For example, a compound of interest may change from one polymorphic form to another, while different crystalline aggregations of the same compound can have different solubility profiles. Impurities can mask the true solubility, and aggregation in solution can also change the thermodynamic equilibrium. Finally, errors which have been published in the literature data may in fact magnify from publication to publication. 

Polymorphism and solvatomorphism are not, of course, limited to small molecules, and such phenomena can be observed in protein crystals as well. Two polymorphic forms of aprotinin have been identified, and the solubility of these studied in a variety of aqueous media [84], The needle polymorph was found to exhibit increased solubility with increased temperature (i.e., an endothermic heat of solution), while the solubility of the bipyramid form decreased by with increasing temperature (i.e., an exothermic heat of solution). The solubility curves crossed at 25 °C for a pH of 4.75, and hence one could obtain the desired crystal form through a judicious selection of crystallization temperature. 

The effect of solvent composition on the solubility of polymorphs is illustrated by cimetidine [128], The onset of melting of the two forms is essentially indistinguishable, making it impossible to apply the conventional nomenclature to the labeling of the polymorphs. Form B was found to be less soluble than form A, identifying it as the more stable polymorph at room... 

In some instances, distinct polymorphic forms can be isolated that do not interconvert when suspended in a solvent system, but that also do not exhibit differences in intrinsic dissolution rates. One such example is enalapril maleate, which exists in two bioequivalent polymorphic forms of equal dissolution rate [139], and therefore of equal free energy. When solution calorimetry was used to study the system, it was found that the enthalpy difference between the two forms was very small. The difference in heats of solution of the two polymorphic forms obtained in methanol was found to be 0.51 kcal/mol, while the analogous difference obtained in acetone was 0.69 kcal/mol. These results obtained in two different solvent systems are probably equal to within experimental error. It may be concluded that the small difference in lattice enthalpies (AH) between the two forms is compensated by an almost equal and opposite small difference in the entropy term (-T AS), so that the difference in free energy (AG) is not sufficient to lead to observable differences in either dissolution rate or equilibrium solubility. The bioequivalence of the two polymorphs of enalapril maleate is therefore easily explained thermodynamically. 

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. 

Figure 5. shows the solubility curves for a monotropic system of two polymorphs and will be used to discuss methods for controlling the polymorphic form of the product. In this instance the thermodynamically stable and thus least soluble polymorph is Form I. 

Ritonavir is a product of Abbott Laboratories Ltd. for the treatment of HIV and is marketed as Norvir , in liquid and semisolid capsule formulations. It received FDA approval for market launch in march 1996, at which time only one polymorphic form of Ritonavir (Form I) was known. Two years later in early 1998 a laboratory responsible for testing the formulated product in the US reported dissolution test failures of the semisolid capsules, and noted that drug product had precipitated out of solution. A new polymorphic form had been discovered that was thermodynamically more stable than the existing form and approximately 5 times less soluble in the formulation. Figure 7. 

Cimetidine is known to crystallize in 5 polymorphic forms and 3 hydrated forms [11]. Solubility data is presented in this reference for Forms A, B and C. Form E was not known at the start of the study in reference [11] and Form D could not be crystallized, suggesting that it is less stable than the other forms. This is confirmed by melting point data which indicates the order of thermodynamic stability close to the melting temperature isEmelting point data for the evaluated forms are presented in Table 3. Form A is the commercially available Form and the desired product for this case study. 

It is recommended that concentration measurements for this type of modeling work are based on analytical standards of mole or mass fraction, to avoid the conversion error caused by density effects. The excess solid phase should always be characterized by a suitable analytical technique, before and after the equilibrium solubility measurements, to confirm that the polymorphic form is unchanged. It should be noted that the crystal shape (habit) does not always change significantly between different polymorphic forms, and visual assessments can be misleading. 

A wide range of physical constants, for instance melting point, boiling point, specific gravity, viscosity, refractive index, solubility, polymorphic forms vis-a-vis particle size, in addition to characteristic absorption features and optical rotation play a vital role in characterization of pharmaceutical chemicals and drug substances. These physical constants will be discussed briefly with typical examples as under ... 

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... 

The rate at which a compound dissolves is dependent upon its surface area, solubility, solution concentration, rate of reaction and transport rate. These quantities are defined as follows surface area - the surface area of the individual particles if the compound is not compressed or the surface area of a disk if the compound is compressed solubility - the solubility of the polymorphic form in the solid phase solution concentration - the concentration of the compound in the bulk of the solution rate of reaction - the rate at which the solid surface reacts with the solvent or dissolution medium transport rate - the rate at which the compound travels through the diffusion layer. The rate of dissolution, or flux, of a compound can be given as ... 

It was mentioned that the solubility is that of the polymorph used to prepare the solid phase. It is possible to achieve higher dissolution rates by using unstable polymorphic forms of the compound. For example, if a hydrate is the stable polymorphic form in the presence of water, an anhydrous form would be more... 

Form I polyammonium catena-polyphosphate contains the shortest long-chain anions of several polymorphic forms having the same chemical composition.1 It is slightly soluble in water and gives a cloudy, viscous solution. The solubility increases with the quantity of solid phase present the apparent solubility of the pure compound at 25° has been estimated to be 0.15 g per 100 g of water.1 The compound is more soluble in hot water or in the presence of other dissolved... 

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