Polymorphism critical size

The rate of nucleation is dependent on the degree of supersaturation as described in section 2.4.1, and because this will always be larger for Form 1 it may be incorrectly assumed that Form I will always precipitate first. The true situation is somewhat more complicated because the critical size, activation energy and nucleation rate also depend on the solid state that is being formed [6]. It is quite feasible and a regular occurrence, that a less stable polymorph will have a higher rate of nucleation than a more stable form, as illustrated in figure 6. 

QbD on stability studies are science and risk-based approach to understanding API physical and chemistry properties. The API s KSAs are typically moisture, solvent content, impurities, polymorph, particle size, stoichiometry, and other attributes specific to the individual API. Risk-based criticality analysis of these KSAs can address their potential influence on the API stability, therefore, help to define the API stability control strategy. " °... 

In the discussion of polymorphism in Chapter 6 several different possible equilibrium transformations from one form to another were outlined. It was pointed out that kinetic factors can also play an important role in determining which polymorph is actually observed under specific conditions. An important factor in the crystallization process is the nucleation step and the free energy barrier that needs to be overcome in order to form a nucleus of critical size. It does not necessarily follow... 

Process validation should be extended to those steps determined to be critical to the quality and purity of the enantiopure drug. Establishing impurity profiles is an important aspect of process validation. One should consider chemical purity, enantiomeric excess by quantitative assays for impurity profiles, physical characteristics such as particle size, polymorphic forms, moisture and solvent content, and homogeneity. In principle, the SMB process validation should provide conclusive evidence that the levels of contaminants (chemical impurities, enantioenrichment of unwanted enantiomer) is reduced as processing proceeds during the purification process. 

In each of the aforementioned studies, qualitative IR spectroscopy was used. It is important to realize that IR is also quantitative in nature, and several quantitative IR assays for polymorphism have appeared in the literature. Sulfamethoxazole [35] exists in at least two polymorphic forms, which have been fully characterized. Distinctly different diffuse reflectance mid-IR spectra exist, permitting quantitation of one form within the other. When working with the diffuse reflectance IR technique, two critical factors must be kept in mind when developing a quantitative assay (1) the production of homogeneous calibration and validation samples, and (2) consistent particle size for all components, including subsequent samples for analysis. During the assay development for... 

Modified from Van Cappellen, 1991). The particle size, j, is critical for the inversion from one polymorphous form to another. 

Standardization problems (L4) arise from the polymorphic nature of apo(a) and from its linkage to apo-B within the Lp(a) lipoprotein. A combination of an anti-apo(a) as capture antibody with an anti-apo-B for detection enables the expression of the Lp(a) concentration as lipoprotein particles. The size of the apo(a) isoforms becomes critical in assays using only apo(a) antibodies, so that the problem of the units of mass for Lp(a) has not been solved yet. 

In essence, the test battery should include XRPD to characterize crystallinity of excipients, moisture analysis to confirm crystallinity and hydration state of excipients, bulk density to ensure reproducibility in the blending process, and particle size distribution to ensure consistent mixing and compaction of powder blends. Often three-point PSD limits are needed for excipients. Also, morphic forms of excipients should be clearly specified and controlled as changes may impact powder flow and compactibility of blends. XRPD, DSC, SEM, and FTIR spectroscopy techniques may often be applied to characterize and control polymorphic and hydrate composition critical to the function of the excipients. Additionally, moisture sorption studies, Raman mapping, surface area analysis, particle size analysis, and KF analysis may show whether excipients possess the desired polymorphic state and whether significant amounts of amorphous components are present. Together, these studies will ensure lotto-lot consistency in the physical properties that assure flow, compaction, minimal segregation, and compunction ability of excipients used in low-dose formulations. 

The demand for small, narrowly distributed particles with well-defined polymorphic form is critical in drug delivery applications, considering the direct role that particle size and polymorphism play in solubility. 

Figure 13.26. Schematic plot of free energy of formation of clusters from solution as a function of size (number of ions in the cluster). Curve A corresponds to the (thermodynamically) ultimately formed more stable phase, while curve B corresponds to the precursor phase. The particle size, j, is critical for the inversion from one polymorphous form to another. (Adapted from Van Cappellen, 1991.)...

Crystallization of lard and PSCO emulsions with similar initial droplet size distributions led to partial coalescence under perikinetic and orthokinetic conditions. The application of shear accelerated the destabilization of the emulsions after the achievement of a critical SFC. The SFC was found not to be the sole contributing factor to emulsion destabilization. Crystal morphology and distribution within the droplet are important factors in the destabilization of these emulsified fats. The emulsions are relatively stable in the short term when crystals are small and form quickly in a consolidated mass in the bulk of the droplet. Polymorphic transitions were not detectable as a source of destabilization in this experiment. The observation of the microstructure of bulk and emulsified fats gave insight into the mechanisms of emulsion destabilization. 

As mentioned in two critical reviews on transcultural psychopharmacology of the TCAs (Pi et al. 1993a Sramek and Pi 1999), the concept of differences between Asian and non-Asian populations in the pharmacokinetics and pharmacodynamics of TCAs has gained support from clinical reports and controlled studies. Whether these differences are due to ethnicity, pharmacokinetics, pharmacodynamics, environmental factors, or shortcomings of study design (such as small sample size) is not definitely known. Although recent studies of CYP polymorphism support the possibility of genetic differences, future studies will need to address these issues. 

The process illustrated here is a simple modification of a previous example. Shown in Fig. 7-25, this modified process prepares the crude ding as a slurry in a feed vessel. The slurry feed was continuously charged to a dissolver that was maintained at a temperature of about 50 C. The feed rate was controlled such that the slurry was put into solution in the dissolver, and the dissolved solution charged continuously to the crystallizer through an in-line filter to remove extraneous insoluble particles and traces of the undissolved product. The crystallizer contained the seed slurry with the correct form at a lower temperature, about 25 C. The crystallizer slurry was continuously filtered through a ceramic cross-flow Alter system with a pore size of 0.2 p-m, and the clear permeate was sent back to the dissolver for further solubilization of product. This was inn until the feed tank was empty and all supersaturation was relieved. The critical parameters for successful development of this process were solubilities of the polymorphs, seeding, and control of supersaturation. 

Many different lanthanides and early transition metals form A3C compounds by this type of reaction, as described for the face-centred cubic iron polymorph. The limiting factor appears to be the size of the radius of A. A critical radius of 1.35 A seems to be required to form the face-centred cubic lattice with twelve coordinate ions at room temperature. 

Definition of the API in terms of its critical quality attributes. Among the attributes that should be considered are chemical purity qualitative and quantitative impurity profiles physical characteristics such as particle size, bulk and tap density polymorphic forms moisture and solvent content homogeneity and microbial quality (if the product is susceptible to microbial contamination). 

The most extreme circumstances where physical parameters are of critical importance are for those materials where different crystalline forms are possible. The different polymorphs may have decidedly different characteristics with regard to crystal shape, size, and most importantly solution characteristics. Many important pharmaceutical chemicals exist in more than one crystalline form, and the manufacturer... 

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