Polymorphic forms of drugs

NIRA provides a non-destructive alternative to differential scanning calorimetry for the determination of polymorphic forms of drugs, e.g. the polymorphic forms of caffeine. NIRA has also been used to determine optical purity. While the pure opposite enantiomers of a substance have identical NIR spectra, mixing two... 

Indicates ratio of solubility of low-melting polymorphic form to solubility of high-melting polymorphic form of drug. 

The basis for reactivity in the solid state lies in molecular mobility and molecular complementarity. Grinding is well known to create lattice defects and amorphous phases,and the formation of polymorphic forms of drugs as a result of these stresses is well documented in the pharmaceutical literature. Therefore, the concepts of solid-state reactivity in pharmaceutical materials can be applied to understanding the formation of cocrystals. 

When the supercritical fluid and drug solution make contact, a volume expansion occurs leading to a reduction in solvent capacity, increase in solute saturation, and then supersaturation with associated nucleation and particle formation. A number of advantages are claimed by using this platform technology (6), such as particle formation from nanometers to tens of micrometers, low residual solvent levels in products, preparation of polymorphic forms of drug, etc. 

Figure 5 Fourier transform-Raman spectra of the two polymorphic forms of drug X with a spectrum of a tablet containing drug X.

Another example in the literature on the preparation of pure polymorphic forms of drug compounds by SCF processing is that of fluticasone propionate, which is also a drug delivered by the respiratory route (27). As the compound decomposes before melting, DSC traces do not give definitive temperature profiles for the transformation between polymorphs I and II. X-ray diffraction patterns, however, have been used to confirm the presence of different polymorphic forms. The drug recrystallizes as form II from solution by the SEDS process in the presence of supercritical carbon dioxide at all temperatures, while form I is obtained by conventional crystallization methods. The rapid nucleation by SCF antisolvent aids in the formation of the metastable form II. A further advantage of SCF... 

Table 53-2. Some important drug reactions due to mutant or polymorphic forms of enzymes or...

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. 

Measurements of the dissolution behavior of polymorphic forms of relatively insoluble drugs are a convenient way of measuring thermodynamic parameters which, in turn, provide a rational approach to selection of the more energetic polymorphic forms of these drugs for absorption. Large differences in free energy... 

MM deVilliers, JG Van der Watt, AP l.otter. Interconversion of the polymorphic forms of chloramphenicol palmitate (CaP) as a function of environmental temperature. Drug Dev Ind Pharm 17(10) 1295—1303, 1991. 

Fig. 11 Plot of the 13C signal intensity as a function of contact time for two distinct methyl resonances of two polymorphic forms of a developmental drug substance.

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. 

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... 

There are nine known human isozymes within the UGT1 family and six within the UGT2 family. Polymorphic forms of some of these enzymes are associated with diseases and significant adverse effects to some drugs. 

Process groups expend considerable effort seeking out different crystal forms of drug candidates. Different polymorphs are often discovered during routine solubility studies as process groups search for an optimal recrystallization solvent. In one such study, a group uncovered 11 different polymorphs, some of which were likely hydrates or other solvates.8... 

Muller et al. determined the structure of />-toluoyl-protected tetrazole nucleoside 50 <2005CEJ6246>. The structures of optically active stereoisomers of antifungal agent 51 were solved <2001CPB1110>. Two polymorphic forms of the drug cilostazol 52 (inhibitor of phosphodiesterase III) have been characterized <2002AXCo525>. 

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