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H Nyqvist

Publications and source records attributed to H Nyqvist.

At least 19 recordsLinked to original sources
PubMed2000

Drug-fatty acid salt with wax-like properties employed as binder in melt granulation.

The tacky and deformable properties of a wax-like drug-fatty acid salt, propranolol oleate (POA), make particle size reduction and separation challenging. The aim of this study was to investigate the use of POA as binder in a melt granulation procedure to improve processing properties. POA is a suitable candidate for binder phase in melt granulation with a melting temperature of 50-56 degrees C. Small batches (ca 30 g) were manufactured using a high shear mixer with lactose monohydrate as the substrate phase. Optimum uniformity of drug content and minimum friability were found at 10% w/w POA binder concentration. POA melt granules exhibited a >10-fold increase in the rate of in vitro dissolution at pH 7.4 with 0.2% w/v sodium lauryl sulphate compared with raw POA. The increased drug surface area in granular form was thought to be responsible for the change in dissolution behaviour. This study has demonstrated that melt granulation using POA as binder is a viable process which leads to beneficial changes in dissolution behaviour for the lipophilic drug-fatty acid salt.

Adrenergic beta-Antagonists↗
PubMed2000

Methods of studying aging and stabilization of spray-congealed solid dispersions with carnauba wax. 1. Microcalorimetric investigation.

Rapidly cooled materials are often unstable as a result of changes in their physical properties due to imperfect crystallization. In the process of spray-congealing, melted material is atomized into droplets which very quickly solidify. This increases the possibility of the material crystallizing in different metastable forms. In this study it is shown that isothermal microcalorimetry can be used to observe the change in the thermodynamic state of spray-congealed carnauba wax during storage. In order to accelerate the thermodynamic change in the spray-congealed wax, three annealing procedures have been developed and compared using isothermal microcalorimetry. By means of annealing, a spray-congealed product closer to a thermodynamically stable state has been achieved.

Calorimetry↗
PubMed2000

Characterization of oleic acid and propranolol oleate mesomorphism using (13)C solid-state nuclear magnetic resonance spectroscopy (SSNMR).

Lipids regularly exhibit complicated thermotropic and lyotropic phase behavior. In this study, the utility of (13)C solid-state nuclear magnetic resonance spectroscopy (SSNMR) in characterizing the phase properties of pharmaceutical lipids was investigated. Variable temperature (13)C SSNMR spectra and spin-lattice relaxation times (T(1)(C)) were obtained for high-purity oleic acid (OA) and propranolol oleate (POA). Spectral changes took place following OA gamma-to-alpha phase transition that indicated increased nuclear inequivalence of aliphatic chain carbons in the alpha phase. T(1)(C) data for the alpha phase demonstrated considerable conformational changes throughout the aliphatic chain, not solely in the methyl side chain as previously reported. These data support alpha-OA classification as a conformationally disordered crystalline phase. The prevalence of low T(1)(C) values in both POA I and II suggested the absence of a rigid crystalline molecular lattice, so both phases were described as conformationally disordered crystalline phases. A two-phase mixture of POA I and II was also identified, emphasizing the sensitivity of this technique. (13)C SSNMR provided valuable information regarding the nuclear environment of specific functional groups in lipid crystalline and mesomorphic structures. Understanding phase behavior at the molecular level can aid selection of appropriate formulation strategies for lipids by allowing prediction of processing properties, and physical and chemical stability. (13)C SSNMR is a powerful technique for pharmaceutical lipid characterization.

Adrenergic beta-Antagonists↗
PubMed2000

Supercritical fluid processing of proteins. I: lysozyme precipitation from organic solution.

The solution enhanced dispersion by supercritical fluid (SEDS) process was used to evaluate the effect of the processing variables on the biological and physicochemical characteristics of lysozyme protein particles produced from an organic solution of dimethylsulfoxide (DMSO) using an experimental design procedure. The processing variables were temperature, pressure, solution concentration and the flow-rates of supercritical carbon dioxide and a protein solution. Solutions of hen egg lysozyme (0.5-1%, w/v) in DMSO were dispersed using supercritical carbon dioxide as the antisolvent, and particles precipitated in a particle formation vessel. The morphology, particle size and size distribution and biological activity of the protein were determined. The precipitates were also examined with high sensitivity differential scanning calorimetry (HSDSC) and high-performance cation-exchange chromatography. The amount of residual DMSO was determined using headspace gas chromatography. Particle size measurements showed the precipitates to be agglomerates with primary particles of size 1-5 microm, containing <20 ppm of residual solvent. The activity of the precipitates varied between 44 and 100% depending on the experimental conditions. The similarity of HSDSC data for unprocessed and processed samples indicated that the SEDS process does not cause major denaturation of lysozyme when prepared from DMSO solutions. By optimising of working conditions, the SEDS process can produce micron-sized particles of lysozyme with minimal loss of biological activity.

Carbon Dioxide↗
PubMed1999

Hydroxypropyl-beta-cyclodextrin inhibits spray-drying-induced inactivation of beta-galactosidase.

The single-step, fast spray-drying process may represent a valuable alternative to the multistep, time-consuming freeze-drying process in the area of formulation and processing of biopharmaceuticals. In this study, we tested the use of sucrose and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) as stabilizing excipients in the spray-drying of a model protein, beta-galactosidase. The solutions were processed using a Büchi 190 cocurrent Mini Spray Dryer at an outlet temperature of 61 +/- 2 degrees C. The powders were redissolved and analyzed for catalytic activity, aggregation, chemical decomposition, and thermal susceptibility as observed by high-resolution calorimetry. Spray-drying significantly inactivated beta-galactosidase. Spray-drying beta-galactosidase in the presence of sucrose did not prevent inactivation. However, after spray-drying beta-galactosidase in the presence of HP-beta-CD, or HP-beta-CD and sucrose, full catalytic activity was exhibited on reconstitution. Furthermore, the reconstituted product was unchanged in terms of molecular weight, charge, and thermal stability. These findings are consistent with a hypothesis that the change responsible for inactivation of beta-galactosidase was mainly a monomolecular, noncovalent change, i. e., the formation of incorrect structures, that arose from surface denaturation. This study clearly demonstrates that cyclodextrins can be useful stabilizing excipients in the preparation of spray-dried protein pharmaceuticals.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1999

Oleate salt formation and mesomorphic behavior in the propranolol/oleic acid binary system.

Thermal analysis of propranolol/oleic acid mixtures prepared by solvent evaporation enabled construction of the binary system phase diagram. This allowed both physical and chemical interactions to be identified, including complex formation at the equimolar composition. An incongruent melting complex with a characteristic reaction point was identified in excess oleic acid compositions, a common property of fatty acid/fatty acid salt binary systems. The equimolar complex was confirmed to be propranolol oleate using infrared spectroscopy. Wide-angle X-ray powder diffractometry demonstrated that propranolol oleate possessed long-range positional order ( approximately 25 A d spacing) accompanied by a degree of disorder over shorter d spacings. Such a pattern suggested mesophase formation, explaining the unctuous nature of propranolol oleate at room temperature. Accurate measurement of the long-range d spacing was achieved using small-angle X-ray scattering, permitting differentiation of the three different phases identified (phase I: 25.4 A, phase II: 24.6 A, phase III: 25.4-25.5 A). The implications of drug fatty acid salt formation and also mesomorphism in pharmaceutical systems are discussed.

Adrenergic beta-Antagonists↗
PubMed1999

A central composite design to investigate the thermal stabilization of lysozyme.

PURPOSE: The formulation and processing of protein drugs requires the stabilization of the native, biologically active structure. Our aim was to investigate the thermal stability of a model protein, lysozyme, in the presence of two model excipients, sucrose and hydroxypropyl-beta-cyclodextrin (HP-beta-CD). METHODS: We used high sensitivity differential scanning calorimetry (HSDSC) in combination with a central composite design (CCD). As indicators of protein thermal stability, the measured responses were the unfolding transition temperature (Tm), the onset temperature of the denaturation (To), and the extrapolated onset temperature (To,e). RESULTS: A highly significant (F probability <0.001) statistical model resulted from analysis of the data The largest effect was due to pH (over the range 3.2-7.2), and the pH value that maximized Tm was 4.8. Several minor but significant effects were detected that were useful for mechanistic understanding. In particular, the effects of protein concentration and cyclodextrin concentration on Tm and To,e were found to be pH-dependent This was indicative of the partially hydrophilic nature of protein-protein interactions and protein-cyclodextrin interactions, respectively. CONCLUSIONS: Response surface methodology (RSM) proved efficient for the modeling and optimization of lysozyme thermal stability as well as for the physical understanding of the protein-sugar-cyclodextrin system in aqueous solution.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1985

Preformulation studies in a drug development program for tablet formulations.

Recently developed techniques were applied in a preformulation program to select a compound and a suitable salt for use in a one-month toxicological test. The program showed that valuable information can be obtained prior to the choice of a compound as a candidate for a solid-dosage form. Information about the physical and mechanical properties of the chosen compound can be obtained with a limited amount of substance, i.e., surface color and hygroscopicity (1-2 g), dissolution rate and solubility (1-2 g), powder properties (1-2 g), and compaction properties (5-7 g).

Chemical Phenomena↗
PubMed1984

Correlation between the bioavailability of microencapsulated bacampicillin hydrochloride in suspension and in vitro microcapsule dissolution.

The relative bioavailability of microencapsulated bacampicillin hydrochloride in suspension was correlated with the in vitro dissolution half-lives of the microcapsules. Simultaneously, a sensory evaluation was performed to evaluate the taste acceptability of the suspension. The in vitro dissolution half-life is directly related to the coating thickness of the microcapsules. The four suspensions of bacampicillin hydrochloride, containing microcapsules with different coating thickness, were given as single 400-mg oral doses to 12 healthy volunteers after overnight fasting using a crossover design with balanced sequences. Bacampicillin is a prodrug of ampicillin, the concentration of which was determined in plasma and urine by bioassay. There were significant inverse linear relationships between the dissolution half-life and plasma peak concentration, area under the curve, and urinary recovery. The terminal exponential disposition phases of the curves were similar for all four suspensions. There was a significant direct linear relationship between the dissolution half-life and overall taste and bitterness. The results show that the mean bioavailability of bacampicillin hydrochloride from a microcapsule suspension can be predicted from an in vitro dissolution half-life. The results also suggest that bacampicillin hydrochloride can be given in a suspension with sufficient microcapsule film thickness to reduce the bitter taste of the drug and still retain adequate bioavailability.

Adult↗