• Archives of Pharmacal Research
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• 제23권4호
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• pp.381-384
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• 2000

It is well recognized that physicochemical properties of drugs are affected by the type of polymorphic crystalline form of drugs. Clarithromycin is known to exist in at least three polymorphic crystalline forms. Since conventional means to obtain the most thermodynamically stable form (Form II) for the antibiotics is known to be associated with a low purity of the stable form, we developed a novel method to improve the purity of the crystalline form by a modification of the preparation process. The new method involved a simple recrystallization of clarithromycin in solvents having 5-12 carbon atoms (e.g., hexane and heptane) or ethers with 4-10 carbon atoms (e.g., isopropyl ether) and, thus, less likely to be associated with the problem in purity of resulting crystal. Differential scanning calorimetry and powder X-ray diffraction were used to compare the crystalline form of the resultant powder with Form IIcrystal prepared by the conventional method. The crystal prepared by the new method was identical to Form IIcrystal of the conventional method as evidenced by the lack of the exothermic peak near 11$0^{\circ}C$ in differential calorimetry scan, indicating that Form IIcrystal could be readily prepared by the new process. Therefore, these data indicated that the improvement in the purity of the Form IIcrystal for clarithromycin as well as a significant cost reduction is likely by the novel method.

• 한국근적외분광분석학회:학술대회논문집
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• 한국근적외분광분석학회 2001년도 NIR-2001
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• pp.1288-1288
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• 2001

X-ray powder diffraction (XRD) is utilized for determination of polymorphism in crystalline organic materials. Though convenient to use in a laboratory setting, XRD is not easily adapted to in situ monitoring of synthetic chemical production applications. Near-Infrared spectroscopy (NIR) can be adapted to in situ manufacturing schemes by use of a source/detector probe. Conversely, NIR is unable to conclusively define the existence of polymorphism in crystalline materials. By combining the two techniques, a novel simultaneous NIR/XRD instrument has been developed. During material's analysis, results from XRD allow for defining the polymorphic phase present, and NIR data are collected as a fingerprint for each of the observed polymorphs. These NIR fingerprints will allow for the development of a library, which can be referenced during the use of a NIR probe in manufacturing settings.

• Archives of Pharmacal Research
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• 제27권3호
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• pp.357-360
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• 2004

Four crystal forms of ketorolac have been obtained by recrystallization in organic solvents under variable conditions. Different ketorolac polymorphs and pseudo polymorph were characterized by X-ray powder diffraction crystallography (XRD), Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). In the dissolution studies in water at $37{\pm}0.5^{\circ}C$ four crystal forms showed different patterns. The solubility of Form I were the highest. The solubility decreased in rank order: Form I> Form II > Form III > Form IV. Form land Form III were shown to have a good physical stability at room temperature for 60 days. However, Form II is converted to Form III and Form IV is converted to Form I after 60 days storage. Therefore, these observations indicate that crystalline polymorphism for ketorolac is readily inter-convertible and the relationship may have to taken into consideration in the formulation of the drug.

• Journal of Pharmaceutical Investigation
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• 제34권6호
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• pp.443-452
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• 2004

Habit is the description of the outer appearance of a crystal. If the environment of a growing crystal affects its external shape without changing its internal structure, a different habit results. Crystal habit and the internal structure of a drug can affect bulk and physicochemical properties, which range from flowability to chemical stability. A polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of the molecules of that compound in the solid state. Chemical stability and solubility changes due to polymorphism can have an impact on a drug's bioavailability and its development program. During crystallization from a solution, crystals separating may consist of a pure component or be a molecular compound. Solvates are molecular complexes that have incorporated the crystallizing solvent molecule in their lattice. When the solvent incorporated in the solvate is water, it is called a hydrate. To distinguish solvates from polymorphs, which are not molecular compounds, the term pseudopolymorph is used. Identification of possible hydrate compounds is important since their aqueous solubilities can be significantly less than their anhydrous forms. Conversion of an anhydrous compound to a hydrate within the dosage form may reduce the dissolution rate and extent of drug absorption. An amorphous solid may be treated as a supercooled liquid in which the arrangement of molecules is random. Amorphous solids lack the three-dimensional long-range order found in crystalline solids. Since amorphous forms are usually of higher thermodynamic energy than corresponding crystalline forms, solubilities as well as dissolution rates are generally greater. A study on crystal form includes characterization of (l)crystal habit, (2)polymorphism, (3)pseudopolymorphism, (4)amorphous solid.

• Journal of Pharmaceutical Investigation
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• 제23권2호
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• pp.81-87
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• 1993

Five crystalline forms of cimetidine, four anhydrous and a monohydrate, have been prepared, and their thermal behavriours have been studied by differential thermal analysis and thermo-gravimetry. The dissolution rates of the five forms were determined in distilled water at $37^{\circ}C$. The results showed a significant difference in the dissolution rate. Polymorphic transformation occurred spontaneously during storage at room condition and was accelerated by applied energy during formulation process-milling.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.228.2-229
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• 2003

Investigation of polymorphism has become a requirement in the pharmaceutical industry because the physical properties and bioavailabilities of crystalline drugs depend on their polymorphic form. Two polymorphic modifications and one pseudopolymorphic modification of cefotaxime sodium were prepared by recrystallization in organic solvents under variable conditions. Four polymorphic modifications of cephardine were prepared by recrystallization. Three polymorphic modifications and one pseudopolymorphic modification of ceftriaxone sodium were prepared by recrystallization. (omitted)

• Journal of Pharmaceutical Investigation
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• 제32권2호
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• pp.73-80
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• 2002

Cefuroxime axetil is a cephalosporin antibiotic having a high activity against a wide spectrum of Grampositive and Gram-negative microorganisms. It is a cephalosporin antibiotic which exist as 2 diastereoisomers: diastereoisomer A and B. It shows polymorphism of three forms: a crystalline form having a melting point of about $180^{\circ}C$, a substantially amorphous form having a high melting point of about $135^{\circ}C$ and a substantially amorphous form having a low melting point of about 70^{\circ}C$. The crystalline form of cefuroxime axetil is slightly soluble in water because diastereoisomer A has lower solubility than B in water. Substantially amorphous form of which there are no difference in solubility between diastereoisomer A and B has better solubility than crystalline form, but it forms a thicker gel than crystalline form upon contact with an aqueous medium. Based on this reason, cefuroxime axetil is not readily absorbable in the gastrointestinal tract, rendering its bioavailability on oral administration very low. The object of this study was to develop an improved non-crystalline cefuroxime axetil composition having a high physicochemical stability and bioavailability. A non-crystalline cefuroxime axetil solid dispersant showing no peak on a Differential Scanning Calorimetry (DSC) scan is prepared by dissolving cefuroxime axetil and a surfactant in an organic solvent; suspending a water-insoluble inorganic carrier in the resulting solution; and spray drying the resulting suspension to remove the organic solvent, said solid dispersant having an enhanced dissolution and stability of cefuroxime axetil and being useful for the preparation of a pharmaceutical composition for oral administration. Tablet was formulated with this cefuroxime axetil solid dispersant, disintegrants and other ingredients. It disintegrated and dissolved easily and dynamically in dissolution medium, so showed a good dissolution profile.

• 약학회지
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• 제41권3호
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• pp.321-327
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• 1997

Investigation of polymorphism has become a requirement in the pharmaceutical industry because the physical properties and bioavailabilities of crystalline drugs depend on their polymorphic form. Five polymorphic modifications and one pseudopolymorphic modification of ecphalothin sodium were prepared by recrystallization, and characterized by UV spectrophotometer, DSC, TGA and X-ray crystallography. The solubilities of all modifications were examined by the disslution test. Form 2 and 1 showed higher solubilities than any other crystal forms. The modifications were also investigated for their stability after storage of 2 months at 100%, 76%, 52% and 0% humidity.

• Journal of Pharmaceutical Investigation
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• 제27권3호
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• pp.233-239
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• 1997

Glibenclamide is a second generation sulfonylurea that is orally active as a hypoglycemic drug. It exists as a crystalline powder which is sparingly soluble in water. It was investigated that the potential of glibenclamide to exhibit polymorphism. Three polymorphic modifications (form 1, form 2 and form 3) and three pseudopolymorphic modifications (form 4, form 5 and form 6) were obtained by crystallization from different organic solvents. The isolated crystal forms were characterized by differential scanning calorimetry(DSC), thermogravimetric analysis(TGA) and X-ray crystallography powder diffraction studies. Form 1 was the most stable and melt at $175.4^{\circ}C$. Form 2 was metastable and melt at $151.0^{\circ}C$. Form 3 was a new polymorphic modification because it was different from form 1 and form 2 in X-ray crystallography powder diffraction data. Form 4 was a 1 : 7(toluene : glibenclamide) toluene solvate; form 5 was a 1 : 5(toluene : glibenclamide) toluene solvate; form 6 was a 3 : 8(pentanol : glibenclamide) pentanol solvate. All forms were stable in 3-month storage under 0% or 100% humidity condition. The dissolution rate of form 4 was highest; those of form 2, form 3, form 1, form 5 and form 6 followed.

• Bulletin of the Korean Chemical Society
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• 제30권9호
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• pp.2007-2010
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• 2009

Donepezil hydrochloride is a reversible acetylcholinesterase inhibitor that is used in the treatment of Alzheimer’s disease to improve the cognitive performance. It shows different crystalline forms including hydrates. Therefore, it is very important to confirm the polymorphic forms in the formulations of pharmaceutical materials because polymorphs of the same drug often exhibit significant differences in solubility, bioavailability, processability and physical/chemical stability. In this paper, four different forms of donepezil hydrochloride were prepared and characterized using X-ray powder diffraction, Fourier transform infrared, and solid-state nuclear magnetic resonance (NMR) spectroscopy. This study showed that solid-state NMR spectroscopy is a powerful technique for obtaining structural information and the polymorphology of pharmaceutical solids.