Crystallization challenges in drug development: scale-up from laboratory to pilot plant and beyond.

Crystallization is one of the most critical unit operations in the pharmaceutical industry. Pharmaceutical companies invest solid form of the drug substance. Rapid development of a candidate depends on the ability to produce desired drug substance with consistent properties as early as possible. This paper discusses the issues related to crystallization process laboratories at various stages in the drug development cycle. Critical issues at each stage of development, recent advances, and crystallization opportunities and their potential are outlined.

Solid-state investigations of erythromycin A dihydrate: structure, NMR spectroscopy, and hygroscopicity.

The crystal structures of the commercially available form of erythromycin A dihydrate and clarithromycin anhydrate, in addition to the structure of erythromycin B dihydrate, are reported in this paper. In light of the crystallographic data, analysis of the structural information provides insight into the physical properties of these pharmaceuticals. The propensity of these pharmaceuticals to form solvated structures is discussed and the hygroscopicity of erythromycin A dihydrate is investigated. Solid-state 13C NMR was used to monitor changes that occur when the dihydrate form of erythromycin A is stored under conditions of low relative humidity. Although erythromycin A dihydrate retains its crystallographic order at low humidity, as indicated by its X-ray powder diffraction pattern, the local chemical environment is dramatically influenced by the loss of the water molecules and results in dramatic changes in its solid-state 13C NMR spectrum.

Mechanistic aspects of chiral discrimination on modified cellulose.

Cellulose and cellulose derivatives are biopolymers which are often used as stationary phases for the separation of enantiomers. Describing the mechanism of such separations is a difficult task due to the complexity of these phases. In the present study, we attempt to elucidate the types of interactions occurring between a diol intermediate for a LTD(4) antagonist and a tris(4-methylbenzoate)-derivatized cellulose stationary phase. Thermodynamic studies indicate that, at low temperatures, the enantioselectivity is entropy driven. At higher temperatures, the separation is enthalpy driven. DSC and IR experiments reveal that the transitions between the enthalpic and the entropic regions of the van't Hoff plots are a result of a change in conformation of the stationary phase. Investigation of chromatographic kinetic parameters reveals that, at low temperature, the second eluted enantiomer undergoes sluggish inclusion interactions. Subtle changes in the structure of the analyte indicates that π-π interactions do not contribute to enantioselectivity. Finally, molecular modeling of (R)- and (S)-diol and the stationary phase suggests that hydrogen bonding is a primary factor in the separation, and the calculated energy values obtained from the molecular modeling correlate well with the chromatographic elution order.

Structure of 5-chloromercurio-2'-deoxyuridine.

Chloro(2-deoxyuridin-5-yl)mercury, [HgCl-(C9H11N2O5)], M(r) = 463.24, monoclinic, P2(1), a = 8.9319 (6), b = 5.7057 (6), c = 12.465 (2) A, beta = 110.70 (1) degree, V = 594.3 (2) A3, Z = 2, Dx = 2.589 g cm-3, lambda(Cu K alpha) = 1.54184 A, mu = 272.61 cm-1, F(000) = 432.0, T = 293 K, final R = 0.034 and wR = 0.047 for 1091 observed reflections.