Makoto Otsuka

Self-modeling curve resolution (SMCR) analysis of near-infrared (NIR) imaging data of pharmaceutical tablets

The idea of quality by design (QbD) has been proposed in pharmaceutical field. QbD is a systematic approach to control the product performance based on the scientific understanding of the product quality and its manufacturing process. In the present study, near-infrared (NIR) imaging is utilized as a tool to achieve this concept. A practical use of a chemometrics technique called self-modeling curve resolution (SMCR) is demonstrated with NIR imaging analysis of pharmaceutical tablets containing two ingredients, a soluble active ingredient, pentoxifylline (PTX), and an insoluble excipient, palmitic acid. Concentration profiles obtained by SMCR reveal that the homogenous distribution of chemical ingredients strongly depends on the grinding time and that its process plays a central role in quantitative control, say sustained-release of PTX. In addition, pure component spectra by SMCR indicate a sequential change of specific NIR peak intensities following the increase of the grinding time. The spectra change shows a molecular structure change related to its crystallinity during grinding process. Accordingly, this study clearly demonstrates that NIR imaging combined with SMCR can be a powerful tool to reveal chemical or physical mechanism induced by the manufacturing process of pharmaceutical products and that it may be a solid solution for QbD of pharmaceutical products.

Effects of bead size and polymerization in PMMA bone cement on vancomycin release

Polymethylmethacrylate (PMMA) bone cement loaded with antimicrobial agents is used for the treatment and prevention of infections in orthopaedic surgery. The use of antimicrobial-loaded bone cement allows for high local doses while avoiding systemic toxicity. The release of vancomycin (VCM) from bone cement has been reported. However, the exact mechanism behind the release is unknown. We studied the influence of bead size and polymerization time on elution, and considered the release mechanism for VCM. We used CMW Endurance Bone Cement. Cements were prepared by mixing 6 g of VCM with 40 g of polymer, and then 10 g of liquid monomer was added. We kneaded and shaped the preparation into spheres containing 10.7 w/w% VCM. We measured the release of VCM from PMMA beads of three different sizes. Average weights of the beads were 0.96 g (SB) (n = 6), 2.86 g (MB) (n = 2) and 5.65 g (LB) (n = 1). Additionally, we studied beads made with different polymerization times. The polymerization time was taken as the period from the making of the beads until the start of the study, and was 15 min (B15), 20 min (B20), 60 min (B60) or 180 min (B180). The release of VCM showed a bimodal curve with a high initial release followed by a sustained release. Regarding the size of the beads, SB released 7.2%, MB released 4.3% and LB released 3.1%. Regarding polymerization time, B15 released 10.0%, B20 released 6.5%, B60 released 6.3% and B180 released 4.3%, respectively. The release of VCM from PMMA beads was influenced by bead size and polymerization time. Those beads which were smaller and had a shorter polymerization time released more VCM. Total pore volume of beads that polymerization time was 30 min after drug-release test was 1.33 times grater than that of control beads that polymerization time was one week before drug-release test. This suggested that the short polymerization time caused the beads to leak more VCM. We proposed a model with four kinds of the dissolution from bone cement. (A) Dissolution from drug particles on the cement surface. This type shows the burst effect of release curve. (B) Dissolution from micropores near the cement surface. It is responsible the grater part of the curve based on Higuchis equation

Prediction of tablet properties based on near infrared spectra of raw mixed powders by chemometrics: Scale-up factor of blending and tableting processes

The purpose of this research was to develop a method of prediction based on near-infrared (NIR) spectra of raw mixed powders before compression by using chemometrical means. The effect of the difference in scale up using a pilot-scale mixing machine and a continuous tableting machine was studied. The formulation consisted of sulpyrine, microcrystalline cellulose, and 1% magnesium stearate. Tablets were obtained in lab-scale and plot-scale experiments. Mixing was performed in 1 and 100 L, respectively. NIR spectra of the raw mixed powders were taken using a NIR spectrometer. The mixed powders were compressed by a compression tester and eccentric-type tableting machine. Tablet hardness in both the lab- and pilot-scale experiments decreased with a increase in mixing time. The variance of tablet mass was evaluated as a coefficient of variation (CV) of tablet weight, and decreased with prolonged mixing. The hardness and CV were evaluated based on the NIR spectra of the raw powdered materials by principal component regression (PCR) in both lab-scale and pilot-scale experiments. The minimum standard errors of cross-validation could be realized by using six- and four principal component models, respectively. Calibration models to evaluate both tablet hardness and CV were obtained based on the NIR spectra of raw mixed powders by using PCR.

Non-invasive and rapid analysis for observation of internal structure of press-coated tablet using X-ray computed tomography.

Background: Since the internal structure of a tablet can be measured without destruction of the sample by X‐ray computed tomography (CT), it could be applied to quality control of tablets during the manufacturing process. Aim: A novel, fast, noninvasive tablet observation method was developed to evaluate the internal structure of commercial press-coated tablets by using X-ray CT. Method: Thirty-two CT image slices of four kinds of commercial press-coated tablets (tablets A, B, C, and D) were measured 300 m interval between edges of the tablet by using an X-ray CT. The thinnest layer thickness of the tablets and distance between centers of gravity (DCG) of tables were calculated. Results: The order of the TLT of the tablets was tablet B > tablet C > tablet D > tablet A. The result indicated that the order of DCG was tablet A > tablet D > tablet C > tablet B. Noninvasive observation of the internal structure of commercial, press-coated tablets by X-ray CT has been demonstrated to be useful in quality control of production. Conclusion: The internal structure of press-coated tablets could be observed without pretreatment, without destruction, and very rapidly by X‐ray CT.

Multivariate analysis of DSC–XRD simultaneous measurement data: a study of multistage crystalline structure changes in a linear poly(ethylene imine) thin film

AbstractA multivariate analytical technique has been applied to the analysis of simultaneous measurement data from differential scanning calorimetry (DSC) and X-ray diffraction (XRD) in order to study thermal changes in crystalline structure of a linear poly(ethylene imine) (LPEI) film. A large number of XRD patterns generated from the simultaneous measurements were subjected to an augmented alternative least-squares (ALS) regression analysis, and the XRD patterns were readily decomposed into chemically independent XRD patterns and their thermal profiles were also obtained at the same time. The decomposed XRD patterns and the profiles were useful in discussing the minute peaks in the DSC. The analytical results revealed the following changes of polymorphisms in detail: An LPEI film prepared by casting an aqueous solution was composed of sesquihydrate and hemihydrate crystals. The sesquihydrate one was lost at an early stage of heating, and the film changed into an amorphous state. Once the sesquihydrate was lost by heating, it was not recovered even when it was cooled back to room temperature. When the sample was heated again, structural changes were found between the hemihydrate and the amorphous components. In this manner, the simultaneous DSC–XRD measurements combined with ALS analysis proved to be powerful for obtaining a better understanding of the thermally induced changes of the crystalline structure in a polymer film. FigureDSC–XRD combined with ALS analysis provides a powerful method for elucidating thermally induced changes of crystalline structure in a polymer film

Long-term therapeutic effect of novel calcium phosphate-based compounds injected in ovariectomized rats

The specific aim of this study was to evaluate the efficacy of well-characterized Mg/Zn/F-CaP preparations (administered by injection) in preventing bone mineral deficiency in ovariectomized (OVX) rats. Donryu rats (4 weeks old, average weight 70 g) were divided into six experimental groups: GN (normal), GC (control, OVX), and OVX rats injected with suspensions of MZF-CaPs (G2, G3, and G4) or with Zn-containing tricalcium phosphate (ZnTCP, G1). The composition of the preparations was G1: 34.1 wt % Ca; 19.5 wt % P; and 6.17 wt % Zn; G2 (#51): 23.7 wt % Ca; 13.6 wt % P; 1.1 wt % Mg; 2.9 wt % Zn, and 1.1 wt % F; G3 (#68): 22.4 wt % Ca; 14.1 wt % P; 2.6 wt % Mg, 2.6 wt % Zn, and 2.3 wt % F; G4 (#76): 28.5 wt % Ca; 15.5 wt % P; 1.9 wt % Mg, 1.8 wt % Zn, and 3.0 wt % F. The suspensions (10 mg/0.2 mL) were injected into the right thigh once a week for 12 weeks. Bone mineral density (BMD) was measured by X-ray computed tomography and bone mechanical strength (BMS) was measured as femoral three-point bending strength. BMD and BMS were significantly higher in the femurs from groups G1, G2, G3, and G4 than from GC. No significant difference was observed in BMD or BMS between the left and right femurs for any group. The results indicate that the injected Mg/Zn/F-CaP compounds were effective in preventing bone loss induced by ovariectomy in rats and suggest that these compounds have potential use for treating osteoporosis.

Influence of crystallite microstrain on surface complexes governing the metastable equilibrium solubility behavior of carbonated apatites.

This study was on the influence of the mineral phase crystallite microstrain (CM) on the nature of the surface complex (SC) governing the metastable equilibrium solubility (MES) behavior of carbonated apatites (CAPs) in aqueous acidic media (0.10 M acetate buffers, with and without fluoride, 0.50 M ionic strength maintained with NaCl). The MES behavior of a set of four CAPs (synthesized at 85 degrees C by a precipitation method) of increasing CM and therefore of increasing MES (CAP4 > CAP3 > CAP2 > CAP1) was quantified. The following were the findings. For CAP1 and CAP2, the SCs deduced were Ca10(PO4)6(OH)2 and Ca10(PO4)6F2 for the nonfluoride and the fluoride cases, respectively. For CAP3 and CAP4, the SCs deduced were Ca9.5(PO4)6OH or Ca9.5(HPO4)(PO4)5(OH)2 and NaCa9.5(PO4)6F2 for the nonfluoride and the fluoride cases, respectively. These results together with that from an earlier limited study show that the Ca/P ratio of the SC decreases from 1.67 to 1.58 to 1.50 with increasing CM of the CAPs; this relationship inversely correlates with the chemistry of maturation of aqueously precipitated defective apatites. Also the SCs do not appear to exist as a continuous series and only a few SCs may account for the MES behavior over a wide range of CAP preparations.

Nano- and macro-geometrical structural change of caffeine and theophylline anhydrate tablets during hydration process by using X-ray computed tomography

The effects of nano- and macro-geometrical factors on the hydration kinetics of caffeine (CA) and theophylline anhydrate (TA) tablets at high humidity were investigated using X-ray high-resolution computed tomography (CT). Hydration profiles of CA and TA tablets obtained at 25 and 50 MPa, 96% relative humidity, and 20 degrees C were measured by weight and X-ray CT. The total tablet volume (G-V) and average tablet density (G-D) calculated based on the volume and weight of tablets, and tablet volume (CT-V) and tablet density (CT-D) were evaluated by X-ray CT. The hydration kinetics of CA and TA tablets followed two-dimensional growth of nuclei (Avrami-Erofee) and three-dimensional phase boundary equations, respectively. The increase in the G-V of TA tablets was initially more than, but later less than, that of CA tablets. The G-D of CA tablets varied extensively and was constant initially, whereas that of TA tablets decreased significantly in the initial stage. The CT-V of CA tablets gradually increased initially, but that of TA tablets increased significantly early on. The inter-granular volume (IG-V) of both tablets decreased initially with large fluctuations, but then increased. The CT-D of CA tablets decreased significantly, but that of TA tablets did not decrease. The hydration kinetics of CA and TA tablets was affected by changes in the geometrical structure of the tablets. X-ray CT is a powerful tool for evaluating dynamic changes inside tablets.

Effect of Dehydration and Urea on Stability of Homosulfamine in Solid States

In the presence of urea in solid states, the stability of unpulverized homosulfamine hydrate (phase I; UHH) is significantly decreased whereas that of unpulverized homosulfamine anhydrate (UHA) is not. The stability of UHH is decreased slightly more by pulverization (PHH). The major objective of this study was to investigate the effects of urea, dehydration, and pulverization on the stability of homosulfamine in solid states. Binary mixtures of UHH and urea, PHH and urea, and UHA and urea in a ratio of 1:1 (wt/wt) were prepared as physical mixtures and were analyzed by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and Fourier transform infrared (FTIR) spectroscopy to study their appearance and structural changes before and after storage. PXRD analysis revealed that physical mixtures comprising UHH and urea and PHH and urea have the same diffraction pattern as that of the mixture of UHA and urea after preparation. The dehydration rate of the crystal water of UHH was accelerated by the presence of urea in addition to pulverization. Moreover, the PXRD patterns of the physical mixtures of UHH/urea and PHH/urea were significantly altered during storage, whereas that of UHA/urea was not, which was consistent with the SEM and FTIR results. The particle shape and appearance of UHH varied significantly as a result of pulverization. The stability of homosulfamine was influenced not only by the presence of urea and dehydration but also by the surface state and particle size of the crystalline form.