Spherical Crystallization for Lean Solid-Dose Manufacturing (Part 1) - Pharmaceutical Technology

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Spherical Crystallization for Lean Solid-Dose Manufacturing (Part 1)
In Part I of this article, the authors describe the materials and methods used in developing a screening strategy to accelerate the preparation and characterization of spherical agglomerates by spherical crystallization.


Pharmaceutical Technology
Volume 34, Issue 3, pp. 72-75

Materials and methods

APIs. Carbamazepine (C15H12N2O), white, crystalline, and prismatic powders, molecular weight (mw) of 236.67 g/mol, melting point (mp) of 191–192 C, reagent grade, Lot 036k1219, and cimetidine (C10H16N6S), white crystalline rod-like powders, mw of 252.34 g/mol, mp of 141–143 C, reagent grade, Lot 088H1317 were purchased from Sigma-Aldrich (St. Louis, MO) and used as received. Phenylbutazone (C19H20N2O2), white, crystalline, and needle-shaped powders, mw of 308.38 g/mol, mp of 106–108 C, purity of 99+ %, Lot A0230775 was purchased from Acros Organics (Morris Plains, NJ) and used as received. Identification tests for carbamazepine and phenylbutazone were carried out by DSC. The use test for cimetidine was performed by FTIR instead of DSC because DSC was unable to distinguish the polymorphs of cimetidine clearly (39).

Solvents. The following sovlents were obtained from Tedia (Fairfield, OH): acetone (CH3COCH3), high-performance liquid chromatographical/spectrometrical (HPLC/spectro) grade with purity of 99.5%, boiling point (bp) of 56 C, mw of 58.08 g/mole, Lot 411050; n-butyl alcohol (CH3 (CH2)3OH), American Chemical Society (ACS) grade with purity of 99.4%, bp of 117.7 C, mw of 74.12 g/mole, Lot 205027; N,N-dimethylformamide (HCON(CH3)2), ACS grade with purity of 99.8%, bp of 153 C, mw of 73.10 g/mole, Lot 020505; n-heptane (CH3 (CH2)5CH3), HPLC/spectro grade with purity of 99.4%, bp of 98 C, mw of 100.21 g/mole, Lot HS-1712 ; isopropyl alcohol ((CH3)2CHOH), HPLC/spectro grade with purity of 99.8%, bp of 82.4 C, mw of 60.1 g/mole, Lot 503027; methanol (CH3OH), HPLC/spectro grade with purity of 99.9%, bp of 64.7 C, mw of 32.04 g/mole, Lot 411070; methyl ethyl ketone (C2H5COCH3), ACS grade with purity of 99.6%, bp of 81.6 C, mw of 72.11 g/mole, Lot 201021; methyl tert-butyl ether ((CH3)3COCH3), certified grade with purity of 99.9%, bp of 55.2 C, mw of 88.15 g/mole, Lot 712032; tetrahydrofuran (C4H8O), HPLC/spectro grade with purity of 99%, bp of 65–67 C, mw of 72.11 g/mole, Lot 411013; and xylene (C6H4 (CH3)2), ACS grade with purity of 98.5%, bp of 137–144 C, mw of 106.17 g/mole, Lot 305065.

The following solvents were obtained from Acros Organics: N,N-dimethylaniline (C6H5N(CH3)2), ACS grade with purity of 99%, bp of 193 C, mw of 121.18 g/mole, Lot A0213203001 and p-xylene (C6H4 (CH3)2), ACS grade with purity of 99%, bp of 138 C , mw of 106.17 g/mole, Lot 48754/2. 1,4-Dioxane (C4H8O2), ACS grade with purity of 98%, bp of 100–102 C, mw of 88.11 g/mole, Lot sp-3432R was obtained from Showa Chemical (Tokyo). Chloroform (CHCl3), HPLC/spectro grade with purity of 99.9%, bp of 60.5–61.5 C, mw of 119.38 g/mole, Lot E554180 and ethanol (CH3CH2OH), HPLC/spectro grade with purity of 99.5%, bp of 78 C, mw of 46.7 g/mole were obtained from Echo Chemical (Taipei, Taiwan). Ethyl acetate (CH3COOC2H5), ACS grade with purity of 99.5%, bp of 76.5–77.5 C, mw of 88.11 g/mole, Lot G43342 was obtained from Grand Chemical (Daejeon, South Korea). Acetonitrile (CH3CN), ACS grade with purity of 99.96%, bp of 81.6 C, mw of 41.05 g/mole, Lot 0043X29B30, and toluene (C6H5CH3), HPLC/spectro grade with purity of 99.8%, bp of 110.6 C, mw of 92.14 g/mole, Lot B46755 was purchased from Mallinckrodt Baker (Phillipsburg, NJ). Reversible-osmosis (RO) water was clarified by a water purification system (Milli-RO Plus, Millipore, Billerica, MA).

Initial solvent screening. Under the initial solvent screening, the 19 solvents specified in the solvents section were chosen. The working procedures followed closely the details described in References 27–30. As previously defined, a good solvent was a solvent that gave solubility of ≥ 5 mg/mL at 25 C. A bad solvent, or antisolvent, was a solvent that gave solubility of < 5 mg/mL at 25 C). The form space was constructed in a framework of 19 X 19 solvent matrix (27–30).

Solvent-miscibility studies. The working logics followed the procedures laid out in References 27–30.

Spherical agglomeration . Good solvents, antisolvents, and bridging liquids were chosen according to the form space of each API. For carbamazepine and phenylbutazone, approximately 30 mg of API were dissolved in 2 mL of a good solvent in a 20-mL scintillation vial. For cimetidine, 2 mL of saturated solution were prepared using a good solvent. Then, 10 mL of an antisolvent were added to all API solutions under a standardized agitation of 200 rpm by an orbital shaker (Model OS-701, TDK , Taipei). The 5:1 volume ratio of the antisolvent to the good solvent was based on a specified cystallization method (11). Crystallization only took place in some of the solution systems.

Two hours after the first appearance of solids, the solids were filtered, oven-dried under a mild condition at 40 C overnight, and characterized for their purity, polymorphism, solvates, and crystallinity by DSC, thermal gravimetric analysis (TGA), and FTIR.


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