Polymorphs conversion

T. Norris, PK. Aldridge and S.S. Sekulic, Determination of end-points for polymorph conversions of crystalline organic compounds using on-line near-infrared spectroscopy. Analyst, 122, 549-552 (1997). 

Oral Solutions and Suspensions Formation of precipitate, clarity for solutions, pH, viscosity, microbial bioburden, extractables, and polymorphic conversion when applicable. Additional tests for suspensions include redispersability, rheological properties, mean size, and distribution of particles. 

Norris, T. Aldridge, P.K. Sekulic, S.S., Determination of End-Points for Polymorph Conversions of Crystalline Organic Compounds Using On-Line Near-Infrared Spectroscopy Analyst 1997, 122, 549-552. 

DeBraekeleer, K. Cuesta Sanchez, F. Hailey, P.A. etal., Influence and correction of temperature perturbations on NIR spectra during the monitoring of a polymorph conversion process prior to self-modelling mixture analysis /. Pharm. Biomed. Anal. 1997, 17, 141-152. 

The solid nature of the excipient may influence the final physical form of the tablet (Byrn et al. 2001), such as a tendency to stick (Schmid et al. 2000), or may induce a polymorphic conversion of the active ingredient (Kitamura et al. 1994). Hence, there have been attempts to develop protocols for the selection of compatible active ingredient-excipient compositions (Serajuddin et al. 1999). For instance, nuclear magnetic resonance spectroscopy has been employed to study the structural changes in epichlorohydrin cross-linked high amylose starch excipient (Shiftan et al. 2000), and has also been used to discriminate between two polymorphs of prednisolone present in tablets with excipients, even at low concentrations (5 per cent w/w) of the active ingredient (Saindon et al. 1993). The characterization of excipients by thermal methods has also been reviewed by Giron (1997). 

It is necessary that the melting curve is obtained with a calibrated DSC using small samples (1-3 mg) and slow scanning speeds (<5K/min, preferably 2K/min). The purity of a compound should be determined at several scanning speeds to ensure that the compound does not imdergo any solid-solid transitions, such as polymorphic conversion or degradation. ... 

DSC and complimentary thermal techniques such as temperature X-ray powder diffraction were used to determine the thermodynamic relationship of the six anhydrous polymorphs of tetracaine hydrochloride. ° The phase diagram of the polymorphic conversion of diflunisal in polyethylene glycol 4000 solid dispersions was obtained as a fimction of polymer content. ... 

A fiber optic probe was used by Blanco et al. for analysis of spasmoctyl samples with the active compound otilonium bromide and cellulose, maize starch, sodium starch glycolate, and glyceryl palmitostearate as excipients. Another study from this group covered the identification, qualification of the substance, and the quantification of the active component. A library search with a comparison to the near-infrared spectra of 163 pharmaceuticals was involved. An on-line monitoring for the determination of the endpoint of polymorph conversions in pharmaceutical processes was recently described further investigations into this field were published and are noted previously. ... 

Differentiation between polymorphs was performed by pattern recognition in 1995 by Aldrich et The actual control of a process was reported in 1998 by DeBraekeleer et al., where they described using PCA, SIMPLISMA, and orthogonal projections to correct for temperature variation during the monitoring of polymorph conversion. This is a real-time, in-line procedure. 

Milling Size reduction to Polymorphic conversion Chemical ability ... 

Roller Dry granulation Polymorphic conversion Chemical stability ... 

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

Figure 1.12 Photomicrographs showing the solution phase polymorphic conversion of orthorhombic paracetamol (needles) to monoclinic paracetamol (prisms and plates). Micrograph (a) was taken at t=0 and (b) was taken at t= 30 min. Scale bars = 250 pm.

Nevertheless, this observation cannot be reproduced because of the polymorphic changes that occur when the drug is stored. Until the challenge of controlling or stabilizing the polymorphism conversion is met, the application of polymorphism in pharmaceuticals will be questionable. The knowledge and data on polymorphism are important to the pharmaceutical industry. Many pharmaceutical problems can be explained or avoided if the concept of polymorphism is understood and methods of detection, control, purification, and isolation are available. 

Oral liquids Solubility, polymorphic conversions, chirality, excipient interactions, chemical stability, photostability, pH effects, and container interactions (e.g., type III glass). 

Salmeterol xinafoate is known to exist in two polymorphic forms, forms I and II. Form I is stable, and form II is the metastable polymorph at ambient temperature. The enthalpies of solution (AHso ) of forms I and II determined from van t Hoff solubility-temperature plots are 32.1 and 27.6 kJ/mol, respectively, and the transition temperature obtained by linear extrapolation of the van t Hoff plots is 99 °C. The enthalpy of polymorphic conversion (AHii i) calculated from the plots of log solubility ratio of polymorphs versus the reciprocal of absolute temperature is negative (—4.55 kJ/mol) (5). However, the change in molar volume (AFu i) due to the conversion is positive. Therefore, according to the Clausius-Clapeyron equation,... 

Solvent-mediated polymorphic conversion in supercritical fluids has been demonstrated for carbamazpine (9) and deoxycholic acid (19). When treated with supercritical carbon dioxide (SCCO2) at 55°C and 350 bar for 6 h, a 1 1 mixture of forms I and III of carbamazepine had its form III content increased to 89% (9). The increase in proportion of form III has been ascribed to the dissolution of form I in supercritical carbon dioxide, followed by recrystallization of the stable form III polymorph. Thermal stress alone would not have induced this conversion (20). Similarly, storage of deoxycholic acid at 60°C for one hour inside a vessel pressurized with SCCO2 at 12 MPa resulted in the appearance of new X-ray diflfaction peaks, indicative of polymorphic conversion (19). 

Since compressed carbon dioxide utilized in SFC is usually moisture free, low water activity or relative humidity is an expected condition in most SFC processes unless modified by the addition of water, and polymorphic conversion in such a relatively moisture-free environment will occur via dehydration if a particular hydrate is involved. 

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