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The purpose of this study was to relate the combination of glass transition temperature (Tg) and temperature of measurement with the mechanical and compaction properties of some test materials.Copolymers with different Tg'S were synthesised by free radical copolymerisation of methyl methacrylate with lauryl methacrylate. Elastic moduli were measured by dynamic mechanical analysis at different strain rates and temperatures. Compaction experiments were performed at different compaction speeds and temperatures.The difference between temperature of measurement and Tg appears to determine both elastic modulus and yield strength completely. They both decrease with decreasing difference between temperature of measurement and Tg and increase with strain rate. At temperatures of measurement higher than the Tg the elastic modulus is extremely low because the materials behave as rubbers. Consequently, the amount of energy stored during compaction decreases when the compaction temperature approaches the Tg and increases with strain rate. When the compaction temperature is higher than the Tg, the amount of stored energy is extremely large. The compaction experiments show that the final tablet porosity is completely determined by stress relaxation phenomena. Consequently, the final tablet porosity follows exactly the same relation as that of stored energy.The final tablet porosity is unequivocally determined by the amount of stored energy. This implies that tablet production at a temperature of about 20 K under the glass transition temperature of the material yields tablets with minimum porosity.

Amylodextrin is a linear dextrin and can be produced by enzymatic hydrolysis of the alpha-1,6 glycosidic bonds of amylopectin. Tablets compacted from pure amylodextrin showed good binding properties and did not disintegrate in aqueous media. Extended and decreasing drug release rates were found for tablets of 300 mg with a diameter of 9 mm containing 70% amylodextrin and 30% theophylline monohydrate, when compacted at 5 kN. Almost-constant drug release rates were obtained for these tablets when compacted at 10 or 15 kN. Nearly constant drug release rates were also shown for amylodextrin tablets with a drug load up to 75% compacted at 10 kN. Both release rate and release profile could be adjusted by selecting tablet thickness and incorporation of either lactose as a highly soluble excipient or talc as a hydrophobic excipient.

Amylodextrin is a suitable excipient for the design of solid controlled-release systems. The release of paracetamol from tablets containing 30% drug and 70% amylodextrin was studied in vitro and in vivo. In vitro dissolution profiles showed almost-constant drug release rates during 8 hr, when measured in 0.05 M buffer, pH 6.8. Peroral administration of the tablets to man showed almost-constant paracetamol plasma levels up to 14 hr, as compared to fast absorption and fast elimination of a reference paracetamol solution. The plasma profiles of eight volunteers demonstrated a small intersubject variability during the first day after tablet administration. Increasing variability and decreasing plasma levels during the second day were caused by excretion of tablets from the bodies. Cumulative input as a function of time showed near-zero-order drug release during the first day. The in vivo results indicate that amylodextrin tablets are not hydrolyzed by alpha-amylase, present in the gastrointestinal tract.

Drug release from fatty suppository bases containing a solid dispersion of diazepam with amylodextrin or a complex of prednisolone with amylodextrin was analyzed in a flow-through model. Being present as a suspension in the fatty base, particles of complex or solid dispersion are transported to the lipid-water interface by sedimentation. After entering the aqueous phase they partially dissolve. The suppositories showed increased drug release compared with the corresponding suppositories containing drug only. Because of the partial solubility of amylodextrin, drug release was lower than the release from drug-cyclodextrin complexes. Use of the soluble fraction of amylodextrin for both the solid dispersion and the complex further enhanced drug release, but it was still below that of drug-cyclodextrin complexes.

The ability of amylodextrin (a linear dextrin) to act as a complexing agent or as a carrier for solid dispersion was evaluated. Blends of amylodextrin with diazepam or prednisolone were freeze-dried and kneaded at elevated temperatures, respectively. The products were analyzed by DSC, X-ray diffractometry, and FTIR spectroscopy. Complex formation with amylodextrin by freeze-drying was found not to occur for diazepam but for prednisolone at a molar ratio of 1 to 1. The freeze-dried product of diazepam with amylodextrin proved to be a solid dispersion. Solid dispersions were formed by both wet (with ethanol) and dry kneading at elevated temperatures of low-melting drugs such as lidocain, diazepam, and methyl-PABA with amylodextrin. No solid dispersions were obtained for high-melting drugs such as prednisolone and salicylic acid. The results point to the formation of solid dispersions by a melting mechanism during the process of kneading at elevated temperatures of low-melting drugs with amylodextrin.

The linear dextrin amylodextrin was prepared by enzymatic hydrolysis from waxy maize. Four metastable amylodextrins were prepared by complexation with different volatile organic compounds. All products showed partial dissolution into water at room temperature, because of dissolution of molecules with a lower DP. X-ray diffractometry revealed a helical conformation with six glucose units per turn for amylodextrin and metastable amylodextrins prepared with small molecules, and a helical conformation with seven glucose units per turn for metastable amylodextrins prepared with larger molecules. All metastable amylodextrins showed a helix with reduced distance between two turns as compared to amylodextrin. Metastable amylose, prepared from Amylose V, showed a helical conformation again with a reduced distance between two turns compared to Amylose V. FTIR analysis indicated a more flexible conformation for Amylose V and metastable amylose than for the amylodextrins.

Naproxen and flurbiprofen form complexes with hydroxypropyl-beta-cyclodextrin; with stability constants of 2207 and 12515 M-1, respectively. However, only small fractions of the drug remain complexed when the drug-cyclodextrin complex is added to plasma in vitro. This result can be explained by albumin effectively competing with cyclodextrin for drug binding and by the simultaneous displacement of the drug from cyclodextrins by plasma cholesterol. Naproxen and flurbiprofen were administered intravenously to rats as cyclodextrin complexes. The disposition in the body of naproxen was not significantly altered by the complexation. This indicates that immediately after administration all drug is removed from the cyclodextrin complex. However, the initial distribution of flurbiprofen was changed upon complexation. Drug concentrations in liver, brain, kidney, and spleen were increased, indicating that hydroxypropyl-beta-cyclodextrin may improve the presentation of the flurbiprofen to biomembranes, as compared with plasma proteins. The effect was transient; 60 min after injection the differences in tissue concentration compared with controls were dissipated. Finally, the importance of protein binding in determining the mode of interaction of cyclodextrins on drug disposition is discussed.

The inclusion complex formation of intravenously administered hydroxypropyl-beta-cyclodextrin and beta-cyclodextrin with endogenous lipids was studied. We tested the hypothesis that complex formation of endogenous cholesterol with cyclodextrins in the bloodstream leads to extraction of cholesterol from the large lipoprotein particles. The relatively small cholesterol-cyclodextrin complexes then leave the bloodstream via capillary pores, and dissociation of the complex in the extravascular compartment finally causes redistribution of cholesterol from blood to tissue. This hypothesis is supported by the following experimental findings. Intravenous administration of cyclodextrins led to a transient decrease in plasma cholesterol levels in a dose-dependent manner, and in vitro cholesterol-cyclodextrin complexes passed dialysis membranes with a molecular weight cutoff of 6000-8000. Further, cyclodextrins increased protein binding of the steroidal drug spironolactone, probably through removal of cholesterol from plasma protein binding sites. Finally, extravascular redistribution was directly demonstrated in histological studies of the kidneys. Glomerular filtration of the cholesterol-cyclodextrin complex is followed by dissociation of the complex in the ultrafiltrate, resulting in cholesterol accumulation in the proximal tubule cells. The cholesterol-beta-cyclodextrin complex has a limited aqueous solubility. Crystallization of this complex in renal tissue might explain the nephrotoxicity of parenterally administered beta-cyclodextrin. The absence of such crystallization might explain the lower nephrotoxicity of hydroxypropyl-beta-cyclodextrin after intravenous administration.

Hydroxypropyl-beta-cyclodextrin was analyzed by HPLC using postcolumn complexation with phenolphthalein and negative colorimetric detection, with a detection limit of 20 micrograms/ml. The pharmacokinetics of beta-cyclodextrin and of hydroxypropyl-beta-cyclodextrin were studied after intravenous administration to permanently cannulated rats. The pharmacokinetic behavior of both cyclodextrins was similar to that of inulin, showing rapid distribution over extracellular fluids. Elimination occurred through glomerular filtration. When a dose of 200 mg/kg beta-cyclodextrin was administered the elimination rate was decreased, probably as a result of nephrotoxicity of beta-cyclodextrin. Within 24 hr after administration most of the cyclodextrin dose was recovered unchanged in urine. After oral administration, only insignificant amounts of intact beta-cyclodextrin were absorbed from the gastrointestinal tract.

A high dosage range drug (acetylsalicylic acid), with different particle size distributions, has been formulated with directly compressible excipients and compressed into tablets. Of the prepared blends, the flow and lubrication properties were investigated. The tablets, containing 500 mg acetylsalicylic acid, were investigated for weight variation, drug content, crushing strength, friability, disintegration time, dissolution rate of the drug and stability after storage for eight weeks at 20‡C and 50% or 85% relative humidity. The results show that knowledge of the properties and interactions of drug, directly compressible excipients and other tablet vehicles makes possible the formulation and compression of different particle size acetylsalicylic acid powders into good quality tablets.

The effect of two disinfectants, chlorhexidine and acetic acid, on host leucocytes and bacteria was studied. At a concentration of 50 mg/l, chlorhexidine was found to be bactericidal without interfering with leucocyte function. A concentration of 500 mg/l of acetic acid was neither leucotoxic nor bactericidal. Effects equivalent to the aforementioned were achieved in serum by increasing the chlorhexidine concentration by a factor of 20 and the acetic acid concentration by a factor of 5. Acetic acid reduced leucocyte function more rapidly than it killed bacteria. On the basis of these findings, chlorhexidine is to be preferred for local application in burn wounds to prevent colonisation and infection.

The effect has been studied of particle size of disintegrants on the disintegration time of tablets, compressed without a lubricant and after mixing the ingredients with magnesium stearate, respectively. The results show for the tablets containing a slightly swelling disintegrant, like potato and rice starch, a decreasing negative effect of mixing with magnesium stearate on the disintegration time of the tablets with decreasing particle size of disintegrant. Only a slight effect of particle size and of mixing time with magnesium stearate on the disintegration of the tablets is found for the tablets containing a strongly swelling disintegrant, like sodium starch glycolate.

The influence of faeces on the activity of 9 antibiotics currently used for selective decontamination of the digestive tract was studied. These in vitro findings showed that the antimicrobial activity is differently affected by the presence and concentration of faeces. Great differences in loss of activity were observed on different microorganisms. Decontaminating drugs which were found to be minimally inactivated in vitro by the presence of faeces are proven to be superior in clinical studies too.