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The effects of particle size and sample weight on the dehyration of lactose monohydrate
Poster Session P3: Tuesday I7 September
The stability of highly concentrated morphine hydrochloride (M) solutions for subcutaneous infusion in terminally ill patients, was investigated. M solutions were prepared in five concentrations: 10, 20. 30. 40 and 50 mg/mL. For each concentration a solution was prepared in water and two isotonic solutions were prepared in the appropriate dilution of NaCl 0.9% and glucose 5%. The solutions were stored in borosilicate glass, polypropylene syringes and PVC containers at 4,22 and 4O’C in the absence of light. Samples were taken immediately after preparation and afler 1, 3.7, 14 days, 1, 2, 3 and after 6 months of storage. All samples were evaluated visually (colour and precipitation) and pH and osmolality were measured. The concentration of M and its possible degradation products (morphine-N-oxide. pseudomorphine and apomorphine) was assayed using a validated HPLC method. Storage at 4-C of M solutions at a concentration above 20 mg/mL should be avoided as in daily practice it was observed that the precipitated M takes a very tong tie (more than 24h) to redissolve. In all samples the pH and osmolality remained nearly unchanged over the study period. In all samples more than 95% of the initial concentration of M was found. The concentration of morphine-Noxide remained allmost unchanged over the study period. The concentration of pseudomorphine strongly increased in the solutions stored at 22 and 40-C but remained allmost unchanged in the solutions stored at 4-C. In none of the samples could apomorphine be detected. The samples with an increased pseudomorphine concentration showed a colour change to dark yellow and brown. This colour change was proportional to the increase in pseudomorphine concentration. The type of reservoir and of solution composition did not influence the degradation of M. This study indicated that concentrated M solutions can still be used for subcutaneous infusion after 6 months of storage at 22-C.
Water vapour affects the majority of pharmaceutically active compounds, often leading to deleterious chemical and/or physical changes. For most dosage forms it is relatively easy to control the water content. The problems are however compounded for injectable products due to the requirement to maintain product purity and sterility. A number of novel methods of drying the contents of injection vials were developed to address these challenges. tnformation on three approaches that are novel, effective, elegant and simple will be presented. Each approach will effectively desiccate the contents of an injection vial rapidly, maintaining product quality, integrity, elegance and sterility.
Using isothermal thermogravimetric analysis, the effect of both particle size and sample weight upon the kinetics of lactose monohydrate dehydration was determined. Variation in sample weight was not responsible for alterations in dehydration mechanism. However, increases in the activation energy of the processes were apparent for smaller sample weights. The data derived for the dehydration of unfractionated and 15&355um sieve size fractions conformed to mathematical equations relating to solid state random nucleation mechanisms. The bulk of the unfractionated sample was composed of the latter sieve size fraction. In contrast, the dehydration of a <45um sieve fraction was consistent with diffusion based mechanisms. The activation energy of dehydration for all samples was calculated to lie within the range 60_1OOKJmoI”, and was independent of the conforming mechanisms. Owing to differences in the dehydration mechanisms between the particle size fractions, comparisons of calculated activation energy values was not attempted. The results of isothermal thermal analysis strongly suggest that sample pre-history and particulate properties such as particle size, sample weight, crystal habit, crystal defects and surface properties significantly influence the dehydration behaviour of polymorphic hydrates. The effects of varying sample pre-history must therefore be investigated in any dehydration kinetic study.
The amino acid L-histidine buffers in the physiological pH range and is compatible with calcium ions. This is essential in the formulation of protein drugs such as factor VIII. The buffer should preferably stay amorphous during freeze-drying in order to avoid pH shift and possibly also act as stabiliser. Development of a formulation for recombinant factor VIII showed that L-histidine functions both as buffer and stabiliser for the protein during freeze-drying and long term storage (1). This study describes the physical state of L-histidine after freeze-drying at pH from 4 to 6 and after 2 years storage at 37°C. The physical state was studied with polarisation microscopy and powder Xray diffraction. Moisture induced crystallisation was studied with microcalorimetry. Freeze-drying of L-histidine at pH 5 and 6 resulted in amorphous cakes, Freeze-drying at pH 7 and 6 also gave amorphous cakes but a number of very thin crystal clusters (about 1 mm diameter) were seen on the surface of the cakes. At pH 4, the cake collapsed. Freeze-drying with a thermal cycle induced ctystallisation at pH 6, but not at 7 and 6. A pH around the pKa of the imidazole ring is suggested to be particularly unfavourable for crystallisation. Samples stored for 2 years at 37°C showed no significant change in visual appearance and were X-ray amorphous. Two samples, freeze-dried at pH 6, were exposed to a relative humidity of 33% at 35°C and they crystallised after 1 and 10 hours, respectively. The specific heat of crystallisation was about 70 J/g. In conclusion, this study showed that the crystallisation of L-histidine during freeze-drying is dependent on the freezing cycle and the pH of the solution. Amorphous L-histidine did not crystallise during storage at low moisture content but crystallised and produced a characteristic X-ray diffraction pattern at increased moisture content. 1. T. Csterberg and A. Fatouros, XlVth Congress of the International Society on Thrombosis and Haemostasis, NY, USA, 1993.
The stability of highly concentrated morphine hydrochloride (M) solutions for subcutaneous infusion in terminally ill patients, was investigated. M solutions were prepared in five concentrations: 10, 20. 30. 40 and 50 mg/mL. For each concentration a solution was prepared in water and two isotonic solutions were prepared in the appropriate dilution of NaCl 0.9% and glucose 5%. The solutions were stored in borosilicate glass, polypropylene syringes and PVC containers at 4,22 and 4O’C in the absence of light. Samples were taken immediately after preparation and afler 1, 3.7, 14 days, 1, 2, 3 and after 6 months of storage. All samples were evaluated visually (colour and precipitation) and pH and osmolality were measured. The concentration of M and its possible degradation products (morphine-N-oxide. pseudomorphine and apomorphine) was assayed using a validated HPLC method. Storage at 4-C of M solutions at a concentration above 20 mg/mL should be avoided as in daily practice it was observed that the precipitated M takes a very tong tie (more than 24h) to redissolve. In all samples the pH and osmolality remained nearly unchanged over the study period. In all samples more than 95% of the initial concentration of M was found. The concentration of morphine-Noxide remained allmost unchanged over the study period. The concentration of pseudomorphine strongly increased in the solutions stored at 22 and 40-C but remained allmost unchanged in the solutions stored at 4-C. In none of the samples could apomorphine be detected. The samples with an increased pseudomorphine concentration showed a colour change to dark yellow and brown. This colour change was proportional to the increase in pseudomorphine concentration. The type of reservoir and of solution composition did not influence the degradation of M. This study indicated that concentrated M solutions can still be used for subcutaneous infusion after 6 months of storage at 22-C.
Water vapour affects the majority of pharmaceutically active compounds, often leading to deleterious chemical and/or physical changes. For most dosage forms it is relatively easy to control the water content. The problems are however compounded for injectable products due to the requirement to maintain product purity and sterility. A number of novel methods of drying the contents of injection vials were developed to address these challenges. tnformation on three approaches that are novel, effective, elegant and simple will be presented. Each approach will effectively desiccate the contents of an injection vial rapidly, maintaining product quality, integrity, elegance and sterility.
Using isothermal thermogravimetric analysis, the effect of both particle size and sample weight upon the kinetics of lactose monohydrate dehydration was determined. Variation in sample weight was not responsible for alterations in dehydration mechanism. However, increases in the activation energy of the processes were apparent for smaller sample weights. The data derived for the dehydration of unfractionated and 15&355um sieve size fractions conformed to mathematical equations relating to solid state random nucleation mechanisms. The bulk of the unfractionated sample was composed of the latter sieve size fraction. In contrast, the dehydration of a <45um sieve fraction was consistent with diffusion based mechanisms. The activation energy of dehydration for all samples was calculated to lie within the range 60_1OOKJmoI”, and was independent of the conforming mechanisms. Owing to differences in the dehydration mechanisms between the particle size fractions, comparisons of calculated activation energy values was not attempted. The results of isothermal thermal analysis strongly suggest that sample pre-history and particulate properties such as particle size, sample weight, crystal habit, crystal defects and surface properties significantly influence the dehydration behaviour of polymorphic hydrates. The effects of varying sample pre-history must therefore be investigated in any dehydration kinetic study.
The amino acid L-histidine buffers in the physiological pH range and is compatible with calcium ions. This is essential in the formulation of protein drugs such as factor VIII. The buffer should preferably stay amorphous during freeze-drying in order to avoid pH shift and possibly also act as stabiliser. Development of a formulation for recombinant factor VIII showed that L-histidine functions both as buffer and stabiliser for the protein during freeze-drying and long term storage (1). This study describes the physical state of L-histidine after freeze-drying at pH from 4 to 6 and after 2 years storage at 37°C. The physical state was studied with polarisation microscopy and powder Xray diffraction. Moisture induced crystallisation was studied with microcalorimetry. Freeze-drying of L-histidine at pH 5 and 6 resulted in amorphous cakes, Freeze-drying at pH 7 and 6 also gave amorphous cakes but a number of very thin crystal clusters (about 1 mm diameter) were seen on the surface of the cakes. At pH 4, the cake collapsed. Freeze-drying with a thermal cycle induced ctystallisation at pH 6, but not at 7 and 6. A pH around the pKa of the imidazole ring is suggested to be particularly unfavourable for crystallisation. Samples stored for 2 years at 37°C showed no significant change in visual appearance and were X-ray amorphous. Two samples, freeze-dried at pH 6, were exposed to a relative humidity of 33% at 35°C and they crystallised after 1 and 10 hours, respectively. The specific heat of crystallisation was about 70 J/g. In conclusion, this study showed that the crystallisation of L-histidine during freeze-drying is dependent on the freezing cycle and the pH of the solution. Amorphous L-histidine did not crystallise during storage at low moisture content but crystallised and produced a characteristic X-ray diffraction pattern at increased moisture content. 1. T. Csterberg and A. Fatouros, XlVth Congress of the International Society on Thrombosis and Haemostasis, NY, USA, 1993.