Physicochemical profiling of nanomedicines using centrifugal field flow fractionation.

Nanomedicines comprise multiple components, and particle density is considered an important property that regulates the biodistribution of administered nanomedicines. The density of nanoparticles is characterized by centrifugal methods, such as analytical ultracentrifugation. Particle size and distribution are key physicochemical and quality attributes of nanomedicines.

Mechanical Characterization of Dissolving Microneedles: Factors Affecting Physical Strength of Needles.

Dissolving microneedles (MNs) are novel transdermal drug delivery systems that can be painlessly self-administered. This study investigated the effects of experimental conditions on the mechanical characterization of dissolving MNs for quality evaluation. Micromolding was used to fabricate polyvinyl alcohol (PVA)-based dissolving MN patches with eight different cone-shaped geometries.

Fabrication and Characterization of Dissolving Microneedles for Transdermal Drug Delivery of Apomorphine Hydrochloride in Parkinson's Disease.

Purpose: We fabricated and characterized polyvinyl alcohol (PVA)-based dissolving microneedles (MNs) for transdermal drug delivery of apomorphine hydrochloride (APO), which is used in treating the wearing-off phenomenon observed in Parkinson's disease.

Methods: We fabricated MN arrays with 11 × 11 needles of four different lengths (300, 600, 900, and 1200 μm) by micromolding. The APO-loaded dissolving MNs were characterized in terms of their physicochemical and functional properties.

Crystallization of Amorphous Nifedipine Under Isothermal Conditions: Inter-laboratory Reproducibility and Investigation of the Factors Affecting Reproducibility.

High inter-laboratory reproducibility is required for conducting collaborative experiments among several laboratories. The primary aim of our evaluation of the physical stability of amorphous drugs, conducted in co-operation with eight laboratories, was to establish a protocol for isothermal storage tests to obtain data of the same quality from all the participating laboratories. Sharing a protocol that contained the same level of detail as the experimental section of general papers was insufficient for high inter-laboratory reproducibility.

Real-time in situ X-ray micro-computed tomography study of the effect of impurities on the crystallization of amorphous nifedipine.

Controlling the physical stability of noncrystalline active pharmaceutical ingredients remains a major challenge in the development of amorphous formulations such as amorphous solid-dispersion (ASD) formulations. To establish new evaluation and formulation strategies, the spatial distribution of the crystal phase in bulk amorphous nifedipine (NFD) was investigated as a model. The crystallization of amorphous NFD and the effect of a deliberately added impurity were investigated using powder X-ray diffraction (PXRD), differential scanning calorimetry and real-time in situ X-ray micro-computed tomography (X-ray CT).

Influence of the crystallization tendencies of pharmaceutical glasses on the applicability of the Adam-Gibbs-Vogel and Vogel-Tammann-Fulcher equations in the prediction of their long-term physical stability.

Amorphization is a powerful approach for improving the aqueous solubility and bioavailability of poorly water-soluble compounds. However, it can cause chemical and physical instability, the latter of which can lead to crystallization during storage, diminishing the solubility advantage of the amorphous state. As there is no standard method for predicting the physical stability of amorphous materials, a long-term stability study is needed in drug development.

Isolation of N-nitrosodimethylamine from drug substances using solid-phase extraction-liquid chromatography-tandem mass spectrometry.

N-Nitrosodimethylamine (NDMA) has been detected in some drug substances and pharmaceutical products containing sartans, ranitidine and metformin, and a potential risk of NDMA contamination exists in other drug substances and their pharmaceutical products. To quantitate NDMA in various drugs having diverse physicochemical properties, a specific, sensitive, and reliable analytical method is required, in addition to methods that can be applied to a class of nitrosamines. We aimed to develop an off-line isolation method for NDMA in drug substances using SPE for quantification with LC-APCI-MS/MS.

Evaluation of Drug Sorption on Laboratory Materials with Abraham Solvation Parameters of Drugs and its Prevention.

Purpose: Undesired drug sorption on laboratory material surfaces reduces the performance of analytical methods and results in the generation of unreliable data. Hence, we characterized the sorption of drugs and evaluated the sorption extent using a linear free energy relationship (LFER) model with Abraham solvation parameters of drugs. Furthermore, to prevent sorption, the effects of additives, such as organic solvents and salts, were evaluated.

[Detection and Analysis of Drug Crystals in Medical Transdermal Patches by Using X-ray Diffraction Measurement].

The crystallization of active pharmaceutical ingredients (APIs) in matrix-type transdermal patches has implications for the rate of drug absorption through the skin and patch adhesion strength. Therefore, the presence or absence and the degree of API crystallinity must be controlled to guarantee the quality of patches. In this study, the utility of laboratory-level X-ray diffractometers for the detection and analysis of crystalline APIs in transdermal patches was investigated using medical patches of tulobuterol and isosorbide dinitrate.

Chemical imaging analysis of active pharmaceutical ingredient in dissolving microneedle arrays by Raman spectroscopy.

The purpose of this study was to develop a quality evaluation method for dissolving microneedle arrays (DMNAs) and determine the spatial distribution pattern of drugs in DMNAs. Raman spectroscopy mapping was used to visualize the drug distribution in DMNAs and drug-loaded polymer films as a model. Powder X-ray diffraction (PXRD) and high-pressure liquid chromatography were also performed to characterize DMNAs.

Discrimination of ranitidine hydrochloride crystals using X-ray micro-computed tomography for the evaluation of three-dimensional spatial distribution in solid dosage forms.

A non-destructive discrimination method for crystals in solid dosage drug forms was first developed using a combination of Raman spectroscopy and X-ray micro-computed tomography (X-ray CT). Identification of the crystal form of an active pharmaceutical ingredient (API) at the appropriate pharmaceutical dosage is crucial, as the crystal form is a determinant of the quality and performance of the final formulation. To develop a non-destructive analytical methodology for the discrimination of solid API crystals in a solid dosage form, we utilized a combination of Raman spectroscopy and X-ray CT to differentiate between ranitidine crystal polymorphs (forms 1 and 2) in tablet formulations containing three excipients.

Cold Flow Evaluation in Transdermal Drug Delivery Systems by Measuring the Width of the Oozed Adhesive.

The objective of this study was to develop a simpler and more practical quantitative evaluation method of cold flow (CF) in transdermal drug delivery systems (TDDSs). CF was forcibly induced by loading a weight on a punched-out sample (bisoprolol and tulobuterol tapes). When the extent of CF was analyzed using the area of oozed adhesive as following a previously reported method, the CF profiles were looked different between the samples 12 mm in diameter subjected to a 0.

[Comparison of Adhesive Properties of Transdermal Patches Distributing in Japan-Tack and Peel Strength].

Forty-four brands of transdermal patches for twelve kinds of active pharmaceutical ingredients (APIs) are available in Japan as of April 30, 2018. Although approximately one-third of the corresponding pharmaceutical interview forms lack information on how to evaluate the adhesive properties of the patches, the peel test, probe tack test, or inclined ball tack test have generally been adopted. This means that it might be difficult to simply compare the adhesive properties among the patches because the testing methods are not unified in some cases.

[Ion-pair HPLC analysis of B vitamins in syrup products in Indonesia].

A training course for analysis of B vitamins in syrup products was undertaken at the National Agency of Drug and Food Control at Jakarta as part of the project to deliver safe drugs to people in Indonesia by Japan International Cooperation Agency. Analytical methods have been developed for quantitative determination of B vitamins by ion-pair high-performance liquid chromatography using 1-hexanesulfonic acid sodium salt. Measurements were performed for two syrup products removed from a drug store in Jakarta to determine the amount of each vitamin B.

[Studies on the food allergenic proteins contained in pharmaceutical excipients].

Most drugs contain pharmaceutical excipients. These are pharmacologically inactive substances used as vehicles for the active ingredients of a medication. Some of these pharmaceutical excipients are produced from allergenic foods (e.

Feasibility of atomic force microscopy for determining crystal growth rates of nifedipine at the surface of amorphous solids with and without polymers.

Amorphous nifedipine (NFD), which has a smooth surface immediately after preparation, was shown to have structures resembling clusters of curling and branching fibers approximately 1 μm wide by atomic force microscopy (AFM) after storage at 25°C. The size of the cluster-like structures increased with storage over time, implying crystal growth. The average elongation rate of the fibers determined by AFM at ambient room temperature was 1.

Differences in crystallization rate of nitrendipine enantiomers in amorphous solid dispersions with HPMC and HPMCP.

To clarify the contribution of drug-polymer interaction to the physical stability of amorphous solid dispersions, we studied the crystallization rates of nitrendipine (NTR) enantiomers with identical physicochemical properties in the presence of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP) and polyvinylpyrrolidone (PVP). The overall crystallization rate at 60°C and the nucleation rate at 50-70°C of (+)-NTR were lower than those of (-)-NTR in the presence of 10-20% HPMC or HPMCP. In contrast, similar crystallization profiles were observed for the NTR enantiomers in solid dispersions containing PVP.

Feasibility of 19F-NMR for assessing the molecular mobility of flufenamic acid in solid dispersions.

The purpose of the present study was to clarify the feasibility of 19F-NMR for assessing the molecular mobility of flufenamic acid (FLF) in solid dispersions. Amorphous solid dispersions of FLF containing poly(vinylpyrrolidone) (PVP) or hydroxypropylmethylcellulose (HPMC) were prepared by melting and rapid cooling. Spin-lattice relaxation times (T1 and T(1rho)) of FLF fluorine atoms in the solid dispersions were determined at various temperatures (-20 to 150 degrees C).

Physical characterization of dibasic calcium phosphate dihydrate and anhydrate.

The dehydration of different commercial brands of dibasic calcium phosphate dihydrate (DCPD; CaHPO(4).2H(2)O) was examined over a range of temperatures and water vapor pressures. To determine the main factors affecting the physical stability of DCPD, the baseline characterization of DCPD and dibasic calcium phosphate anhydrate (DCPA; CaHPO(4)) was conducted by thermogravimetric analysis, differential scanning calorimetry and X-ray diffractometry.

Miscibility of nifedipine and hydrophilic polymers as measured by (1)H-NMR spin-lattice relaxation.

The miscibility of a drug with excipients in solid dispersions is considered to be one of the most important factors for preparation of stable amorphous solid dispersions. The purpose of the present study was to elucidate the feasibility of (1)H-NMR spin-lattice relaxation measurements to assess the miscibility of a drug with excipients. Solid dispersions of nifedipine with the hydrophilic polymers poly(vinylpyrrolidone) (PVP), hydroxypropylmethylcellulose (HPMC) and alpha,beta-poly(N-5-hydroxypentyl)-L-aspartamide (PHPA) with various weight ratios were prepared by spray drying, and the spin-lattice relaxation decay of the solid dispersions in a laboratory frame (T(1) decay) and in a rotating frame (T(1rho) decay) were measured.

Significance of local mobility in aggregation of beta-galactosidase lyophilized with trehalose, sucrose or stachyose.

Purpose: The purpose of this study is to compare the effects of global mobility, as reflected by glass transition temperature (T(g)) and local mobility, as reflected by rotating-frame spin-lattice relaxation time (T(1rho)) on aggregation during storage of lyophilized beta-galactosidase (beta-GA).

Materials And Methods: The storage stability of beta-GA lyophilized with sucrose, trehalose or stachyose was investigated at 12% relative humidity and various temperatures (40-90 degrees C). beta-GA aggregation was monitored by size exclusion chromatography (SEC).

Crystallization rate of amorphous nifedipine analogues unrelated to the glass transition temperature.

To examine the relative contributions of molecular mobility and thermodynamic factor, the relationship between glass transition temperature (T(g)) and the crystallization rate was examined using amorphous dihydropyridines (nifedipine (NFD), m-nifedipine (m-NFD), nitrendipine (NTR) and nilvadipine (NLV)) with differing T(g) values. The time required for 10% crystallization, t(90), was calculated from the time course of decreases in the heat capacity change at T(g). The t(90) of NLV and NTR decreased with decreases in T(g) associated with water sorption.

Degradation rate of lyophilized insulin, exhibiting an apparent Arrhenius behavior around glass transition temperature regardless of significant contribution of molecular mobility.

The relative influences of chemical activation energy and molecular mobility in determining chemical reactivity were evaluated for insulin lyophilized with alpha,beta-poly(N-hydroxyethyl)-L-aspartamide (PHEA), and compared with that for insulin lyophilized with trehalose, which had been found to have the ability to decrease the molecular mobility of insulin at low humidity. The ratio of the observed rate constant k(obs) to the chemical activation energy-controlled rate constant k(act) (k(obs)/k(act)) at glass transition temperature (T(g)) was estimated to be approximately 0.6 and 0.

Physical stability of amorphous acetanilide derivatives improved by polymer excipients.

Crystallization rates of drug-polymer solid dispersions prepared with acetaminophen (ACA) and p-aminoacetanilide (AAA) as model drugs, and polyvinylpyrrolidone and polyacrylic acid (PAA) as model polymers were measured in order to further examine the significance of drug-polymer interactions. The crystallization of AAA and ACA was inhibited by mixing those polymers. The most effective inhibition was observed with solid dispersions of AAA and PAA.

Beta-relaxation of insulin molecule in lyophilized formulations containing trehalose or dextran as a determinant of chemical reactivity.

Purpose: The purpose of this study was to elucidate whether the degradation rate of insulin in lyophilized formulations is determined by matrix mobility, as reflected in glass transition temperature (Tg), or by beta-relaxation, as reflected in rotating-frame spin-lattice relaxation time (T1rho).

Methods: The storage stability of insulin lyophilized with dextran was investigated at various relative humidities (RH; 12-60%) and temperatures (40-90 degrees C) and was compared with previously reported data for insulin lyophilized with trehalose. Insulin degradation was monitored by reverse-phase high-performance liquid chromatography.