Kuniko Otsuka

Relation Between Polymorphic Transformation Pathway During Grinding and the Physicochemical Properties of Bulk Powders for Pharmaceutical Preparations

AbstractThe polymorphic transformation pathway during grinding of cephalexin (CEX), chloramphenicol palmitate (CPP) and indomethacin (IMC) were investigated. CEX was converted into noncrystalline solid at room temperature. The meta-stable forms B and C CPP was transformed into stable form A at room temperature. IMC was transformed into noncrystalline solid during grinding at 4°C, but it transformed into meta-stable form a during grinding at 30°C. The melting point (mp) of CPP and IMC were about 90°C and 160°C, respectively. CEX does not have the mp, but have the decomposition point at 190°C. The mp of CEX is higher than the decomposition point. The order of the mp for these drugs is CPP < IMC < CEX. The proportional relation between the mp and the glass transition point of the drugs had reported, therefore, in general the higher mp material has the higher glass transition point. The order of the stability for a noncrystalline solids of these drugs is CPP < IMC < CEX. The noncrystalline solid of CEX is ver...

Effect of Tableting Pressure and Geometrical Factor of Tablet on Dehydration Kinetics of Theophyline Monohydrate Tablets

AbstractThe effect of compression pressure and geometrical factors (thickness and diameter) of tablet on the dehydration kinetics of theophylline monohydrate tablets was studied using an infrared water-content measuring instrument. The dehydration rate of 2 cm diameter tablets decreased with increase in tabletting pressure. The dehydration rates of tablets also depended on tablet shape. The 2 cm diameter tablets (thin tablets) dehydrated faster than 1 cm diameter tablets (thick tablets). Dehydration of the powder bed (loosely packed tablets) and 2 cm tablets compressed at 49 MPa followed the two-dimensional phase boundary equation, and that of 2 cm diameter tablets compressed at 98 MPa and 196 MPa (thin tablets) followed the three-dimensional phase boundary equation. Dehydration of 1 cm diameter tablets compressed at 98 MPa (thick tablets) followed the one-dimensional diffusion equation. It seems that the dehydration of the tablet was controlled by the porosity and the surface area of the tablet. Therefor...

Determination of cephalexin crystallinity and investigation of formation of its amorphous solid by chemoinformetrical near infrared spectroscopy

The crystallinity of cephalexin (CEX) was evaluated by chemoinformetrical near infrared (NIR) spectroscopy. The molecular interaction of ground amorphous solid of CEX was investigated by the method. Six kinds of standard material with various degree of crystallinity were prepared by the physical mixing of crystalline and ground amorphous CEX. X-ray powder diffraction profiles and NIR spectra were recorded for the standard samples. Chemoinformetric analysis was performed on the NIR spectral data sets by principal component regression (PCR). The correlation between the actual and the predicted crystallinity of CEX using the conventional X-ray diffraction method showed a straight line relationship with a slope of 1.000, an intercept of −5.77 × 10−4 and a correlation coefficient of determination (R2) of 0.986. A NIR spectrum of amorphous CEX showed significantly different peaks at 1530 and 1620 nm due to the NH2 group from those of crystalline CEX. PCR was performed on various kinds of pre-transformed NIR spectral data sets of standard samples of CEX. To minimise the standard error of cross-validation (SECV), the spectral data sets were subjected to the leave-one-out method. The combination of normalization and multiplicative scatter correlation treatments yielded the lowest SECV values. Based on a three-components model, a plot of the calibration data between the actual and CEX crystallinity predicted by the NIR method was obtained. The plot showed a straight line (Y = 0.993X + 0.262; R2 = 0.992; n = 18). The mean bias for the NIR and X-ray powder diffraction methods were calculated to be 3.40 and −1.58% and their mean accuracy were 7.70 and 5.76%, respectively. NIR spectral changes of crystalline CEX during grinding suggested the intermolecular hydrogen bonds between the amino and the carboxyl groups are destroyed and the crystals are transformed into the amorphous CEX.

Comparative evaluation of bioactivity change of crystalline trypsin during compression by chemoinformatics and 2-D Fourier-transform infrared spectroscopy

The purpose of this study is to develop a method of evaluating the enzymatic activity of trypsin in a solid-state based on Fourier transform infrared (FT-IR) spectra using chemoinformatics and two-dimensional (2-D) correlation spectroscopy. Crystalline trypsin powders are compressed at 0-4000 kg cm-2 by a compression/tension tester. The enzymatic activity of trypsin is assayed by the kinetic degradation method. Spectra of 10 calibration sample sets are recorded 3 times with a FT-IR spectrometer. The maximum intensity of FT-IR spectra and enzymatic activity of trypsin decrease as the compression pressure increases. The FT-IR spectra of trypsin samples are subjected to a principal component regression (PCR). A plot of the calibration data obtained is made between the actual and predicted trypsin activity based on a two-component model with gamma2=0.909 (n=30). The regression vector is almost the same as the loading vector for PC1. On the other hand, a generalized two-dimensional (2-D) correlation spectroscopic method is applied to FT-IR spectra of compressed trypsin. The result is consistent with that of the chemoinformatics method. The FT-IR chemoinformatics method allows for solid-state quantitative analysis of the bioactivity of the bulk powder of a polypeptide drug.

Dissolution Medium Responsive Simvastatin Release from Biodegradable Apatite Cements Drug Delivery System - The Therapeutically Effect and their Histology in Osteoporosis Rats -

A biodegradable drug delivery system was established using an apatite cement containing simvastatin. The in-vitro drug release from apatite with lower-crystallinity was investigated under simulated osteoblast and osteoclast conditions (SOB and SOC). Apatite cement containing 6% simvastatin had lower crystallinity as the same as natural bone. In-vitro drug release tests were performed under SOB in simulated body fluid (pH 7.8), and then under SOC in acetate buffer (pH4.5) at 37.0｡C, and the process repeated twice. The device had lower drug release rates under SOB, but significantly higher rates under SOC. The simvastatin release rate was 15 times higher under SOC than SOB. The device showed dissolution medium responsive drug release. After implantation of the APC containing simvastatin in osteoporosis rats, the bone mineral density was evaluated by the X-ray computed tomography. The result indicated that the bone mineral density of APC implanted rat was significantly higher than that of control diseased.

Therapeutic Effect of Selected Biomaterials (Mg/Zn/F-CaPs, Administered by Injection) on Bone Properties of Ovariectomized Rats

The purpose of this study was to evaluate the efficacy of magnesium (Mg), zinc (Zn) and fluoride (F)-containing calcium phosphate compounds (Mg/Zn/F-CaP) in correcting the bone mineral deficiency noted in ovariectomized (OVX) rats. In order to evaluate therapeutic effect of selected Mg/Zn/F-BCP preparations (G2: 1.13%Mg/13.6%Zn/2.5%F, G3:7.76%Mg/1.89%Zn /3.01%F and G4:2.72%Mg/3.75%Zn/1.35%F), suspensions consisting of Mg/Zn/F-CaP preparations and of Zn-TCP (G1: 6.17%Zn) powder were injected in the right thigs of OVX rats for 4 weeks. Injection of Zn-TCP powder suspension in G1 and G2 groups led to the recovery of plasma Zn levels in OVX rats. The area under the curve of plasma Zn for the G2, G1 and Normal (not ovariectomized) control group (GN) groups were significantly lower than those of the group G3, G4 and OVX /untreated control (GC) groups (p<0.05). The bone mineral density (BMD) of the right femur was significantly higher than that of the left in G1, G2, G3 and G4 groups on day 28. However, there was no significant difference in the BMD between the left and right femur in the GC and GN groups.

A Comparison of the Technical Quality of American and Japanese Ranitidine Tablets

The purpose of this study was to compare the technical quality of commercial American and Japanese ranitidine tablets. Five brands of 150-mg USP tablets and six brands of 150-mg JP tablets were compared on hardness, friability, average weight, average content, content uniformity, and dissolution. The difference in hardness between American and Japanese tablets was significant. Dissolution profiles of Japanese tablets were not significantly different from one other, whereas those of American tablets were significantly different. However, all brands complied with USP 27. Since all brands can be expected to be in therapeutic use, this result supports the use of the USP criterion as an indicator for therapeutic efficacy.

Predictive Evaluation of Pharmaceutical Properties of Ulinastatin-Containing Vaginal Suppositories as a Hospital Preparation by Near-Infrared Spectroscopy

A vaginal suppository containing ulinastatin (UTI) was developed as a hospital pharmacy product from UTI injection solution and Witepsol® S-55. After mixing at 50°C for 0-8 h, UTI suppositories were prepared, which had good UTI content uniformity. Because 2% surfactant was contained in S-55, the UTI injection solution formed a water-in-oil type emulsion as a suppository base. The measured residual moisture content (loss on drying (LOD)) in the prepared vaginal suppositories decreased as the mixing time increased, but their hardness (hardness test (HT)) increased. Near (N) IR spectra of UTI suppositories were measured after mixing for 0-8 h. The best calibration models to predict the HT and LOD of the suppositories were determined based on the NIR spectra by the leave-one-out method in a partial least-squares regression analysis (PLS). The validation result indicated that PLS models for HT and LOD were obtained based on the spectra treated by a combination of smoothing and normalized, respectively, and the model consisted of three latent variables. The plots between the predicted and measured pharmaceutical properties (HT and LOD) based on the calibration data were superimposed with those of the external validation data. The developed NIR spectroscopy method was applied to the preparation process monitoring for UTI vaginal suppositories. In the prepared vaginal suppositories, the predicted LOD decreased as the mixing time increased, and the measured LOD values superimposed well with the predicted values. In contrast, the predicted HT increased as the mixing time increased, and the measured values superimposed with the predicted values.

Rapid identification of oral solid dosage forms of counterfeit pharmaceuticals by discrimination using near-infrared spectroscopy

BACKGROUND Since it can take an enormous amount of time and cost to discriminate counterfeit medicines by using conventional methods, counterfeit medicines has been spread in the world markets. OBJECTIVE The purpose of this study was to develop a rapid and simple analytical method to discriminate counterfeit drugs using near infrared (NIR) spectroscopy. METHODS Seven types of brand name tablet and generic tablets containing atorvastatin calcium sesquihydrate (AT) preparations were used as simulated counterfeit medicines. NIR spectra of 35 AT tablet products were measured using a diffuse reflection method. RESULTS The NIR spectral data were analyzed by principal component analysis (PCA). The PCA results suggested that the model had sufficient accuracy to discriminate the 7 types for AT tablets. The NIR spectral data were also analyzed using a soft independent modeling of class analogy (SIMCA) method. Predicting the classification of the AT tablet samples was performed based on all the validated AT tablet data using the SIMCA model, and the probability of classification of 7 types was 100%. The discrimination power spectrum of the SIMCA model indicated significant patterns based on diluents. CONCLUSIONS The PCA and SIMCA classification of the AT tablets were depended on the major excipient combinations.

Therapeutic effects of transdermal systems containing zinc-related materials on thermal burn rats

OBJECTIVE The aim of the present study is to evaluate the efficacy of slow zinc (Zn) release from β-tricalcium phosphate powder (ZnTCP) containing 10 mol% Zn on rats with thermal burns. METHODS The first-aid tapes were contained zinc sulfate (ZnSO4) solution, ZnTCP suspensions or zinc oxide ointment. After thermal burn treatments were performed on Zn-deficient rats, the groups D1, D2 and D3 were treated with tapes containing ZnTCP, ZnSO4 and zinc oxide ointment. The effects of the tapes on wound area, plasma Zn levels and alkaline phosphatase activity (Alp) were investigated. RESULTS The wound area profiles of all rat groups could be separated into before and after the scab formation at around day 6. The area under the curve (Aw-AUC) for wound area profiles, therefore, was evaluated as an index of therapeutic scores for the thermal wound. The order of Aw-AUC was D3>C>D2>D1. The degree of expansion at the initial stage by thermal burns of group D1 was the lowest and that of group D2 was the highest, and the order was D1