Drug substance crystallinity

Chemical development Proof of structure and configuration are required as part of the information on chemical development. The methods used at batch release should be validated to guarantee the identity and purity of the substance. It should be established whether a drug produced as a racemate is a true racemate or a conglomerate by investigating physical parameters such as melting point, solubility and crystal properties. The physicochemical properties of the drug substance should be characterized, e.g. crystallinity, polymorphism and rate of dissolution. 

In recent years, with growing concern about the relative bioavailabilities of different samples of the same drug substance, polymorphism has become of prime interest. Miyazaki and co-workers (23) have reported the existence of two crystalline forms of CTC-HCl. The X-ray powder diffraction patterns, IR spectra, dissolution behaviors, and hygroscopicities that they reported were distinctly different and there were discrepancies in the bioavailabilities. 

Other studies have used quantitative XRPD to evaluate the degree of crystallinity in bulk drug substances, such as calcium gluceptate [36], imipenum [37], cefditoren pivoxil [38], and a Lumaxis analog [39]. 

When the excipient matrix in a formulation is largely amorphous, similar XRPD methods can be used to determine the amount of crystalline drug substance present in a drug product. The principles were established in a study that included a number of solid dose forms [40],... 

XRPD as a stability-indicating assay method When the phase identity, or degree of crystallinity (or lack thereof), of a drug substance is important to its performance in a drug product, XRPD can serve as a vital stability-indicating assay method. There is no doubt that XRPD can be validated to the status of any other stability-indicating assay, and that one can use the usual criteria of method validation to establish the performance parameters of the method. This aspect would... 

A new drug substance may exist in a multitude of crystalline and salt forms with different physical properties such as shape, melting point, and solubility that can profoundly impact the manufacturing and performance of its dosage form. 

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... 

Some drug substances can form mesophases with or without a solvent [19-26]. In the absence of a solvent, an increase in temperature causes the transition from the solid state to the liquid crystalline state, called thermotropic mesomorphism. Lyotropic mesomorphism occurs in the presence of a solvent, usually water. A further change in temperature may cause additional transitions. Thermotropic and/or lyotropic liquid crystalline mesophases of drug substances may interact with meso-morphous vehicles as well as with liquid crystalline structures in the human organism. Table 1 presents drug substances for which thermotropic or lyotropic mesomorphism has been proved. 

The solubilization of a drug substance in monophasic liquid crystalline vehicles gives semisolid formulations which are preferably used for topical application (see Surfactant Gels and Transdermal Patches above). 

Figure 13. Screw extruders extrude poorly when the proportion of water soluble compounds, such as mannitol or lactose, reaches 50% or higher. Such formulations are better extruded with low-shear basket extruders (28). As the solubility increases from 5% to 30%, the percent of water needed for extrusion could decrease by up to 25%. This has implications for scale-up, as early lots of drug substance may have a different crystallinity or solubility profile than pilot lots.

Hancock BC, Carlson GT, Ladipo DD, Langdon BA, Mullarney MP. Comparison of the mechanical properties of the crystalline and amorphous forms of a drug substance. Int J Pharma 2002 241 73-85... 

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). 

Change in crystalline form of the drug substance, if the drug is in suspension. 

Any qualitative and quantitative changes in an excipient beyond the ranges noted in level 2 change Change in crystalline form of the drug substance, if the drug is in suspension... 

It is important to characterize the physicochemical properties of the suspensions well, so that the PK data can be interpreted appropriately. Typical characterization of the drug substance includes purity, residual solvents, aqueous solubility pro Lie (pH 2, FaSSIF), crystallinity (XRPD/DSC), particle size, pl and logP. For solution formulations at various stages of discovery studies, dose analysis is essential, and for efLcacy assessment and toxicology studies, chemical stability for the... 

Historically, the administration of crystalline APIs has mainly found use in parenteral applications associated with intramuscular and subcutaneous injections as well as topical applications of suspensions containing micronized APIs. Commercially marketed pharmaceuticals categorized as suspensions for parenteral administration are illustrated in Table 17.3. Many of these products utilize drug substance size reduction in order to promote dissolution following administration. The degree... 

---