Surfactant-facilitated crystallization of dihydrate carbamazepine during dissolution of anhydrous polymorph

The influence of two structurally different anionic surfactants on the anhydrous-to-dihydrate transformation of carbamazepine (CBZ) was investigated. The surfactants studied were sodium lauryl sulfate (SLS), a surfactant commonly used in compendial dissolution methods, and sodium taurocholate (STC), an important surfactant in the solubilization and absorption of drugs and lipids in the gastrointestinal tract. Results show that both surfactants promoted the crystallization of CBZ dihydrate [CBZ(D)] during dissolution of the anhydrous monoclinic polymorph [CBZ(A)]). Examination of crystal surfaces showed that SLS facilitated the surface-mediated nucleation of CBZ(D) on CBZ(A) crystals at surfactant concentrations below the critical micelle concentration (cmc). Solubilization of a dye and related color changes provided visual evidence for adsorbed SLS assemblies on CBZ(A) crystal faces below the cmc. Above the cmc, both surfactants promoted the transformation by increasing the bulk nucleation of CBZ(D). STC changed the crystal morphology of CBZ(D) from acicular to prismatic, depending on STC concentration. Such morphology changes originate from interactions between STC and molecular structures of CBZ(D) crystal faces that interfere with the formation of a hydrogen-bonded chain of water molecules and carboxamide dimers. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:449–460, 2004Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34510/1/10496_ftp.pd

Crystallization pathways and kinetics of carbamazepine–nicotinamide cocrystals from the amorphous state by in situ thermomicroscopy, spectroscopy, and calorimetry studies

The work presented here was motivated by the premise that the amorphous state serves as a medium to study cocrystal formation. The molecular mobility inherent to amorphous phases can lead to molecular associations between different components such that a single crystalline phase of multiple components or cocrystal is formed. Cocrystallization pathways and kinetics were investigated from amorphous equimolar phases of carbamazepine and nicotinamide using hot-stage polarized microscopy (HSPM), hot-stage Raman microscopy (HSRM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). Nonisothermal studies revealed that amorphous phases generate cocrystals and that thermal history affects crystallization pathways in significant ways. Two different pathways to cocrystal formation from the amorphous phase were identified: (1) at low heating rates (3°C/min) a metastable cocrystalline phase initially nucleates and transforms to the more stable cocrystalline phase of CBZ–NCT, and (2) at higher heating rates (10°C/min) individual components crystallize, then melt and the stable cocrystalline phase nucleates and grows from the melt. Isothermal studies above the T g of the amorphous equimolar phase also confirm the nucleation of a metastable cocrystalline phase from the amorphous state followed by a solid phase mediated transformation to the stable cocrystalline phase. Cocrystallization kinetics were measured by image analysis and by thermal analysis from small samples and are described by the Avrami–Erofeev model. These findings have important implications for the use of amorphous phases in the discovery of cocrystals and to determine the propensity of cocrystallization from process-induced amorphization. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1147–1158, 2007Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55996/1/20945_ftp.pd

Formation and physicochemical properties of crystalline and amorphous salts with different stoichiometries formed between ciprofloxacin and succinic acid

YesMulti-ionizable compounds, such as dicarboxylic acids, offer the possibility of forming salts of drugs with multiple stoichiometries. Attempts to crystallize ciprofloxacin, a poorly water-soluble, amphoteric molecule with succinic acid (S) resulted in isolation of ciprofloxacin hemisuccinate (1:1) trihydrate (CHS-I) and ciprofloxacin succinate (2:1) tetrahydrate (CS-I). Anhydrous ciprofloxacin hemisuccinate (CHS-II) and anhydrous ciprofloxacin succinate (CS-II) were also obtained. It was also possible to obtain stoichiometrically equivalent amorphous salt forms, CHS-III and CS-III, by spray drying and milling, respectively, of the drug and acid. Anhydrous CHS and CS had melting points at ∼215 and ∼228 °C, while the glass transition temperatures of CHS-III and CS-III were ∼101 and ∼79 °C, respectively. Dynamic solubility studies revealed the metastable nature of CS-I in aqueous media, resulting in a transformation of CS-I to a mix of CHS-I and ciprofloxacin 1:3.7 hydrate, consistent with the phase diagram. CS-III was observed to dissolve noncongruently leading to high and sustainable drug solution concentrations in water at 25 and 37 °C, with the ciprofloxacin concentration of 58.8 ± 1.18 mg/mL after 1 h of the experiment at 37 °C. This work shows that crystalline salts with multiple stoichiometries and amorphous salts have diverse pharmaceutically relevant properties, including molecular, solid state, and solubility characteristics.Solid State Pharmaceutical Cluster (SSPC), supported by Science Foundation Ireland under grant number 07/SRC/ B1158

How cocrystals of weakly basic drugs and acidic coformers might modulate solubility and stability

Cocrystals of a weakly basic drug (nevirapine) with acidic coformers are shown to alter the solubility dependence on pH, and to exhibit a pH(max) above which a less soluble cocrystal becomes more soluble than the drug. The cocrystal solubility advantage can be dialed up or down by solution pH