Christina Graffner

Calcium alginate matrices for oral multiple unit administration: IV. Release characteristics in different media

Abstract The release properties of calcium alginate minimatrices were studied in media of various compositions. Three drugs with different aqueous solubility (paracetamol, theophylline and chloramphenicol) were incorporated as model substances and their release rates were investigated in 0.1 M HCl and water. The theophylline release was also studied in simulated gastric fluid (SGF), simulated intestinal fluid (SIF), 0.034 M NaCl and 0.1 M NaCl. Additionally, the simultaneous liberation of calcium ions from the carrier material into the different media was analysed and illustrated by means of calcium release curves. Only when pure water was applied as release medium were the matrices able to extend the release of the two least soluble model drugs, theophylline and chloramphenicol. In all other media the drug release proceeded much more rapidly, due to various transformations in the carrier material. The cross-linking calcium ions were rapidly discharged from the matrices in the presence of acid, and the carrier material was converted to alginic acid. Although the transformation did not change the morphology or the swelling behaviour of the matrices, it destroyed their ability to provide retarded drug release. In the NaCl solutions and SIF, the calcium ions were partly exchanged by the non-gelling sodium ions or sequestered by the phosphate. This caused swelling and, in the latter case, dissolution of the matrices, and induced a rapid release of the encapsulated drug. Due to the pronounced sensitivity towards the composition of the release medium and the rapid drug release in media of physiological relevance, it was concluded that the minimatrices do not seem applicable as an oral controlled release system.

Calcium alginate matrices for oral multiple unit administration: III. Influence of calcium concentration, amount of drug added and alginate characteristics on drug release

Abstract The influence of the calcium concentration, the amount of drug added and the characteristics of the alginate on the encapsulation and release of theophylline from minimatrices made of calcium alginate were studied. The combined effects of the calcium concentration used for gelation and the amount of drug added during matrix production was investigated by means of a central composite design. Both factors influenced the drug encapsulation and drug release rate in water. The response surfaces for the release parameters t 50% and T d showed that the slowest release was obtained from matrices prepared using intermediate levels of the two factors. The retardation was, however, relatively small, and t 50% and T d did not exceed 1.5 and 2.8 h, respectively. Drug release in 0.1 M HCl was very rapid from all the formulations tested. It was only slightly affected by the amount of drug added during matrix production and was not influenced by the calcium concentration. A high G alginate was used as carrier material in the matrices investigated during the central composite design. Alginates containing fewer G residues gave matrices with a lower encapsulation efficiency and a faster drug release rate in both dissolution media. An increase in the mean molecular weight of the alginate from 200 000 to 270 000 did not affect the release properties.

Calcium alginate matrices for oral multiple unit administration: II. Effect of process and formulation factors on matrix properties

Abstract Small calcium alginate matrices were prepared by ionotropic gelation of droplets of an alginate solution containing dispersed theophylline, followed by air-drying of the gel beads. The effect of various production factors on the size, composition and drug release properties was investigated in two separate studies. A 2 3 factorial design and a 2 V 5−1 fractional factorial design were applied. The size of the matrices was controlled mainly by the coaxial airstream applied during droplet production. However, the alginate concentration and the calcium concentration used for gelation also appeared to have a significant influence. The latter two factors, together with the amount of drug dispersed, determined the matrix drug content. The calcium concentration and the amount of drug affected matrix calcium content the most. The amount of drug also affected the moisture content. The calcium and alginate concentrations, the gelling time, the drug addition and the alginate G content affected the drug release rate in water. An increase in the level of all these factors caused a retardation in release. Several synergistic two-factor interactions were also observed.

Water solid interactions II. Effect of moisture sorption and glass transition temperature on compactibility of microcrystalline cellulose alone or in binary mixtures with polyvinyl pyrrolidone

The relation between the moisture sorption and compaction properties of microcrystalline cellulose, MCC, and binary mixtures of MCC with polyvinyl pyrrolidone, PVP, has been examined. PVP is a completely amorphous polymer, whereas MCC contains various fractions of amorphous structure depending not only on the quality used but also on the pharmaceutical processing. The tensile strength of tablets of MCC is shown to depend upon the relative humidity, RH, prior to compaction. At an RH of about 70%, a decrease in strength is observed corresponding to the upward shift of the moisture sorption isotherm. For a dry blend of MCC and PVP as well as for a granulation, the tensile strength is determined by the properties of MCC at humidities below 70% RH. At humidities above 70%, a reduction of the glass transition temperature of PVP below the operating temperature (20°C) is the dominating factor, resulting in a decrease in tensile strength.

Water-Solid Interactions. III. Effect of Glass Transition Temperature, Tg, and Processing on Tensile Strength of Compacts of Lactose and Lactose/Polyvinyl Pyrrolidone

The effect of moisture sorption at different relative humidities on the tensile strength and the physical stability of compacts of crystalline and partly amorphous lactose, alone and in binary mixtures with PVP, has been studied. Furthermore, the role of moisture as a plasticizer and its effect on the glass transition temperature, Tg, are related to the compactibiltiy. Samples were conditioned for 2 hr using a climate test chamber at different relative humidities. Moisture sorption was determined, the radial crushing strength for compacts was measured immediately and after storage, and the tensile strength was calculated. The glass transition temperature, Tg, was determined using DSC. The tensile strength of the compacts was found to depend on both the conditioning humidity and the humidity during storage. An increase in humidity to a level at which the glass transition temperature, Tg, fell below the operating temperature, T, resulted in transition from a rigid glassy state to a mobile rubbery state. For compacts of partly amorphous lactose, an increase in the tensile strength was observed during storage of tablets, due to recrystallization of the amorphous regions above Tg. Tablets of mixtures of lactose and PVP exhibit a sharp decrease in tensile strength at humidities above 70% RH, due to the glass-to-rubber transition of PVP.

Water-solid interactions. I: A technique for studying moisture sorption/desorption

Abstract Moisture sorption and desorption have been characterized for active (naproxen and paracetamol) and inactive pharmaceutical solids by using a climatic test chamber. The relative humidity (RH) of the climatic test chamber was varied in the range from 15 to 90%. Equilibrium moisture content was achieved within a period of 2 h for slightly hygroscopic and moderately hygroscopic substances. For very hygroscopic substances equilibrium was reached within 2 h at low RH ( 60%). Moisture sorption isotherms were characterized by using the climatic test chamber and were found to be identical with moisture sorption isotherms characterized by desiccators.

Comparative dissolution studies of rectal formulations using the basket, the paddle and the flow-through methods: II. Ibuprofen in suppositories of both hydrophilic and lipophilic types

Abstract The applicabilities of the paddle, basket and flow-through methods have been investigated for four different rectal compositions of both hydrophilic and lipophilic types containing ibuprofen. The formulations were studied with respect to in vitro dissolution rate and behaviour in the different apparatus. The reproducibility of the three techniques was also tested by using a hydrophilic and a lipophilic composition. None of the techniques appeared to be more applicable than the others for the compositions tested, though the dissolving suppositories are less sensitive to the technique used than the melting ones. It has been found necessary to consider the behaviour of the product, with regard to its composition and the in vitro method used, when judging the applicability of a dissolution test for a rectal dosage system. Comparison to our previous data on paracetamol also shows that the physical-chemical properties of the drug substance are of great importance, and must be considered, when the judgement of applicability is made.

Influence of amount of hard fat in suppositories on the in vitro release rate and bioavailability of paracetamol and codeine. I. A comparison of three suppository compositions in vivo

Abstract The flow-through cell at a flow rate of 16 and 8 ml/min has been used to investigate how the amount of paracetamol and codeine phosphate, in relation to the total weight of a lipophilic suppository, influences the in vitro dissolution rate. Two in vivo studies explored how the rate and extent of bioavailability in humans varied as a function of fraction of drug substances. Despite an approx. 20-fold difference in aqueous solubility between paracetamol and codeine phosphate, the lipophilicity controlled the in vitro release and bioavailability. Decreasing the amount of paracetamol and codeine phosphate in relation to total suppository weight and increasing the size of the suppository resulted in a faster absorption rate and an increased extent of bioavailability. This was more pronounced for paracetamol. The flow-through cell was found to produce dissolution profiles which were in agreement with the plasma concentration profiles obtained, indicating that the lower flow rate reflected the in vivo situation more correctly than the higher flow rate. The intra-individual variation when administering one composition on two different occasions was found to be relatively small for five of the subjects who participated in both studies.

Influence of amount of hard fat in suppositories on the in vitro release rate and bioavailability of paracetamol. II: A comparison between three compositions and a rectal solution

Abstract The flow-through cell has been used to investigate whether it is possible to discover any relationship between the in vitro dissolution rate of paracetamol from suppositories and the plasma concentrations reached after administration to eight healthy volunteers. A rectal solution was used as a reference. Three suppository compositions were varied with regard to amount of drug substance in relation to total suppository weight and size. The in vivo study was designed to explore the use of statistical moment analysis and convolution/deconvolution in the association of in vivo data and in vitro dissolution results. An increase in both rate and extent of bioavailability was observed when decreasing the fraction and increasing the size, but it was not explained to what degree each of these factors contributed. The flow-through method using a 22.6 mm cell, primarily developed for oral dosage forms, was found to produce dissolution profiles which associated well with the plasma concentration profiles obtained both when a statistical moment analysis and the convolution method was applied. The most optimal flow rate studied was 28 ml/min which reflected the in vivo situation better than a lower or a higher flow rate.

Biopharmaceutical studies of naftidrofuryl in hydrocolloid matrix tablets

Abstract Absorption studies have been performed in nine healthy volunteers. Plasma concentrations of naftidrofuryl have been compared following administration of a single dose in three modified release explorative hydrocolloid matrix tablets and in an aqueous solution. The solution and one matrix tablet contained 100 mg, whereas the other two matrix formulations contained 300 mg of the drug. The amount of hydrocolloids used in the matrix tablets was varied to produce different in vitro release rates. The relative extent of bioavailability from the 300 mg tablet with a rapid drug release in vitro was significantly reduced, while it was unchanged from tablets with a comparatively slower drug release. This suggests that the absorption process has a limited capacity, and that the drug release rate is not controlling the absorption at this dose level. In contrast, the in vivo release rate from the 100 mg tablet, estimated by means of numerical deconvolution, showed a close agreement with the in vitro data.