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The aim of this study was to evaluate film-formation properties of a novel, organic solvent-free aqueous dispersion of potato starch acetate (SA; degree of substitution 2.8) and its ability to control drug release from a coated tablet. Initially, film-formation mechanisms and drug permeabilities of both organic solvent and dispersion-based SA free films (prepared by cast or spraying techniques) were investigated. The SA dispersion was suitable for the fluid-bed coating process, forming strong films with complete coalescent polymeric spheres. The model compounds predominantly permeated via the micro-pores of SA free films, which resulted from the leaching of water-soluble excipients from the dispersion. Thus, the permeation rate depended on the film structure rather than the physico-chemical properties of the penetrant. In the case of SA-coated tablet, drug release was sustained when the coating level was increased (from 12% to 20%, stated as a weight gain), and also as lipophilicity of the drug increased. When compared to the reference polymer dispersion (Surelease®), SA coatings showed better mechanical properties against the osmotic pressure caused by a hydrophilic core tablet. These results clearly demonstrate that SA dispersion has high utility as a novel aqueous coating material for controlled release products.

Drug-carrier particle interactions greatly affect the detachment of drug from the carrier in inhalation powders. In this study, a novel multiple dose, reservoir-based Taifun was used as a dry powder inhaler, and the effects of carrier physical properties were evaluated on the pulmonary deposition of budesonide, along with physical stability of the inhalation powder. In this study, untreated commercial preparation of alpha-lactose monohydrate, highly amorphous spray dried lactose, crystallized spray dried lactose, Flowlac-100 and Flowlac-100 mixed with crystalline micronized lactose were used as carriers. Dry powder formulations were prepared by the suspension method, where the budesonide-carrier ratio was 1:15.1 (w/w). Carriers and formulations were initially characterized, and again after 1 month's storage at 40 degrees C/75% RH. The physical properties of the carriers strongly affected the pulmonary deposition of budesonide and the physical stability of the inhalation powder. Initially, amorphous contents of the carriers were 0-64%, but spontaneous crystallisation of the amorphous lactose occurred during storage and, thus all carriers were 100% crystalline after storage. When compared to an untreated alpha-lactose monohydrate, the highly amorphous spray dried lactose and Flowlac-100 did not improve aerosol performance of the inhalation powder. When crystalline spray dried lactose was used as a carrier, the highest RF% values were achieved, and RF % values did not alter during storage but the emitted budesonide dose was lower than the theoretical dose. When Flowlac-100 mixed with crystalline micronized lactose was used as a carrier, the emitted budesonide dose was close to the theoretical dose, and high RF % values were achieved but these changed during storage.

In the present study, the effects of ethanol to water ratio in feed solution on the physical properties of spray-dried alpha-lactose monohydrate were evaluated. Crystallinity of the spray-dried lactose was determined by isothermal microcalorimetry (IMC) and by differential scanning calorimetry (DSC). Water content of the spray-dried lactose was determined by thermogravimetric analysis and the surface area was evaluated by Brunauer, Emmett, and Teller (BET) method. The crystallinity of spray-dried lactose varied from 0% to 100%, depending on the ratio of ethanol to water in the feed solution. Lactose spray dried from pure ethanol was 100% crystalline and contained hydrate water. Lactose spray dried from pure water was 100% amorphous. The feed solution substantially affected the ratio of surface water to hydrate water, as the content of surface water increased and hydrate water decreased, while the crystallinity of spray-dried lactose decreased. Surface area of the spray-dried lactose increased as a function of amorphous content.

The aim of this study was the evaluation of starch acetate (SA) powders used as tablet excipients. Deformation during powder volume reduction, strain-rate sensitivity, intrinsic elasticity of the materials, and tensile strength of the tablets were examined. Results showed that SA with the lowest degree of substitution (ds) still possessed characteristics of native starch granules. Due to dissolution in synthesis, the properties of higher ds SAs depended on precipitation and drying processes. The acetate moiety, perhaps in combination with existing hydroxyl groups, was a very effective bond-forming substituent. The formation of strong molecular bonds increased, leading to a very firm and intact tablet structure. Small changes existed in compression-induced deformation due to acetylation. Some fragmentation was induced due to the slightly harder and more irregular shape of high-substituted SA particles. The plastic flow under compression was enhanced. Acetylated material was slightly less sensitive to fast elastic recovery in-die, but somewhat more elastic out-of-die. In spite of their superior bonding, SAs under compression behaved similarly to native starches. It was concluded that deformation properties were more the consequence of the molecular chain structure properties of the starch polymer than the effect of the acetate moiety itself. In contrast, the opposite seemed to be the case with the extensive improvement in bond-forming properties.

Starch acetates (SA) have been investigated as novel, multifunctional excipients for the direct compression tableting process. In this study, the film-forming ability of SA (DS 2.8) and the effect of commonly used plasticizers on the physical properties of SA films were evaluated. The results were compared with the properties of ethylcellulose (EC). Free films were prepared by a solvent-cast method. Mechanical studies, water vapor and drug permeability tests, and thermal analysis (DSC) were used to characterize the film-forming ability of SA and efficiency of tested plasticizers. SA films were tougher and stronger than EC films at the same plasticizer concentration. Also, in most cases, the water vapor permeability of SA films was lower than that of EC films. DSC thermograms supported the findings of the tensile test: plasticizers with several small ester groups (e.g., triacetin and triethyl citrate) were the most compatible with SA. Due to the good mechanical properties, low water vapor, and drug permeabilities of the films, SA seems to be a promising film-former for pharmaceutical coatings. The toughness of SA films may result from their dense film structure, which is due to strong interaction forces between adjacent SA molecular chains.

Relationships between solid-state, densification and compact properties of theophylline monohydrate (TMO), a mixture of forms (TMIX), and anhydrous polymorphs I (TA-I) and II (TA-II) were evaluated. Solid-state identification of powders and compacts was accomplished by powder X-ray diffraction. A compaction simulator was used to assess deformation behaviour of the powders and to prepare compacts. Porosity and tensile strength of the compacts were determined after 1,24, and 168 h of storage at 22% relative humidity. TA-II was stable, whereas TA-I, TMIX and TMO partially transformed to the TA-II form during storage. All theophylline modifications primarily deformed by plastic flow. Increased water content decreased resistance towards densification and deformation of TMIX and TMO when compared to TA-II or TA-I, demonstrating viscoelasticity. Permanent densification behaviours of TMIX and TMO approached to that of TA-II during storage. Tensile strength of the different theophylline forms were practically equal after 1 h of storage. Tensile strength and porosity of TMIX and TMO compacts increased during the storage. Dynamic solid-state transformations from TMO, TMIX and TA-I to TA-II were associated with parallel changes in their densification and compact properties. The extent of these changes was also dependent on the materials' water content.

The physicochemical and tableting properties of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and its tolbutamide (TBM) complex were studied. The kinetics of TBM/HP-beta-CD inclusion complex formation in solution were determined by the phase solubility method. Solid complexes were prepared by freeze-drying and spray-drying. Water sorption-desorption behaviour of the materials were studied and compacts were made using a compaction simulator. TBM and HP-beta-CD formed 1:1 inclusion complexes in aqueous solution with an apparent stability constant of 63 M(-1). HP-beta-CDs and TBM/HP-beta-CD complexes were amorphous whereas the freeze-dried and spray-dried TBMs were polymorphic forms II and I, respectively. Sorption-desorption studies showed that HP-beta-CDs were deliquescent at high relative humidities. TBM/HP-beta-CD complexes had slightly lower water contents at low relative humidities than the physical mixtures. However, at high humidities their water sorption and desorption behaviours were similar to those of corresponding physical mixtures, indicating a glass transition of the complexed materials. TBM/HP-beta-CD complexes demonstrated a worse compactability than similarly prepared HP-beta-CDs or physical mixtures. Also particle properties that resulted from these preparation methods affected the compactability of the materials. In conclusion, the physicochemical and tableting properties of HP-beta-CD were modified by complexation it with TBM.

Purpose. In polymeric coatings, plasticizers are used to improve the film-forming characteristic of the polymers. In this study, a computerized method (VolSurf with GRID) was used as a novel tool for the prediction plasticization efficiency (β) of test compounds, and for determining the critical molecular properties needed for polymer plasticization.

The feasibility of the water-activated, pH-controlled silicone reservoir devices for transdermal administration was investigated using timolol maleate as a model drug. Timolol patches were applied to the arm of 12 volunteers for 81 h, two patches per subject. Timolol absorption from patches was compared to that from a peroral timolol tablet formulation (Blocanol((R)) 10 mg). Furthermore, in vivo plasma levels of timolol were compared with those predicted by kinetic simulations. Skin irritation induced by timolol patches was assessed by visual scoring and color reflectance measurements. With water-activated, pH-controlled patches both steady-state concentrations of timolol in plasma and its duration could be controlled. However, a considerable, inter-individual variability in the transdermal absorption of timolol was observed. This is due to the high fractional skin control in timolol delivery. Timolol patches were well tolerated by subjects. Skin irritation induced by the combination of timolol with long-term occlusion was mild, and after removal of the patches, skin changes were practically reversed in 24 h. Simulation model was useful in prediction of timolol levels in plasma after transdermal administration.

Previously, transdermal patches with internal pH-controlled release were described. The aim of this study was to test the suitability of the patch design in transdermal delivery and, further, to select such transdermal patch formulations to a clinical study with timolol. In vitro release of timolol from the patches was determined as well as timolol permeation across the human cadaver skin. The effect of the skin on drug release were evaluated in vitro. In vitro data and pharmacokinetic parameters from the literature were used to construct a pharmacokinetic model for the prediction of in vivo performance of the devices. With water-activated, pH-controlled silicone reservoir devices, both the rate of drug release and the duration of constant release were controlled. The rate of timolol release was decreased when the devices were placed on human cadaver skin, and thus, the skin partly controls the rate and extent of timolol delivery to the systemic circulation in vivo. On the basis of in vitro data and kinetic simulations, devices of 10-cm(2) volume releasing timolol in vitro at the rates of 119 and 10 microgh(-1)cm(-2) were selected for human tests.

Stomach-specific drug delivery systems would be of value in treating diseases of the upper gastrointestinal tract. The present study measured in vitro and in vivo drug release from pH-sensitive membrane bags, constructed of poly(acrylic acid) grafted onto a poly(vinylidene fluoride) (PAA-PVDF) membrane, which might be suitable for stomach-specific drug delivery. The used model drugs were propranolol-HCl (1.0 mg) and FITC-dextran MW 4400 (1.0 mg). Drug release in vivo was studied by inserting membrane bags into the stomach and proximal duodenum of anesthetized rats and dogs. At 30 and 180 min, the bags were removed from the lumens and residual drug content was determined. The release of either propranolol or FITC-dextran were comparable in both stomach and duodenum, showing that in vivo drug release did not depend on environmental pH. In vitro results suggested that these results could be explained by interactions between PAA and the mucous layers of the stomach and duodenum.

Purpose. The deformation behaviors of compressedfreeze-dried and spray-dried tolbutamide/hydroxypropyl-β-cyclodextrinmolecular dispersions were evaluated and compared with similarly preparedtolbutamides (TBM), hydroxypropyl-β-cyclodextrins (HP-β-CD) and astheir physical dispersions.

Ion exchange resins have several applications in pharmacy for controlled or sustained release of drugs. In the present study, effects of the ionic strengths of adsorption medium and dissolution medium on drug adsorption onto and release from a acrylic acid grafted poly(vinylidene fluoride) (PAA-PVDF) were studied. Despite their porosity, PAA-PVDF membranes act reasonable well as cation exchange membranes. It was observed, that ionic strength of adsorption medium, degree of grafting and concentration of propranolol-HCl in adsorption medium affect propranolol-HCl adsorption onto the membrane. The fluxes of smaller molecules (MW500) across the membrane decreased with ionic strength of buffer solution, whereas the fluxes of the large molecules (FITC-dextran, MW 4400) increased with ionic strength. Release rate of adsorbed propranolol-HCl from the membrane into phosphate buffer was greatly affected by ionic strength of adsorption medium. These results can be explained by a cation exchange process between membrane and cations present in the buffer solution and swelling behavior of the grafted PAA chains.

The optical surface quality of pharmaceutical tablets was inspected using a computer-generated hologram based sensor. The image information was related to the optical surface quality of pharmaceutical compacts compressed using different tableting powders as matrix materials for drugs. The role of the compression and thermomechanical properties caused by sensing laser beam on the surface quality are discussed.

Poly( N -isopropylacrylamide) (poly(NIPAAm)) is a temperature sensitive polymer, which has been used in the development of thermally controlled devices. In the present study, poly(NIPAA)m grafted poly(vinylidene fluoride) (PVDF) membranes were prepared by an irradiation method and fluxes of model compounds across the various grafted membranes were measured. The effectiveness of various grafted membranes to control drug fluxes by temperature was studied using FITC-dextrans (molecular weights 4400–50 600) and mannitol as model compounds. Also, the effect of environmental conditions on the LCST of the membrane was evaluated. The fluxes of bigger molecules across a temperature sensitive, porous poly(NIPAA)m–PVDF membranes were effectively controlled by temperature, environmental ionic strength and degree of grafting of the membrane, while flux of the smaller molecules was not controlled thermally even at high degree of membrane grafting. These result indicates that the studied membranes are useful in controlling the permeation of high molecular weight compounds such as polynucleotides, peptides and proteins.

Porous ion exchange membranes have potential applications for drug delivery systems. Permeability of these membranes can be controlled by environmental factors like pH and ionic strength but also the drug properties have an important role in the permeation process. In this paper the influence of the drug charge, lipophilicity and molecular weight on the diffusional drug flux is demonstrated. The membranes under study were poly(acrylic acid) (PAA) grafted porous poly(vinylidene fluoride) (PVDF) membranes which are cation selective due to the partial ionization of carboxyl groups in grafted PAA chains. At low pH the membrane pores are open and the drugs can diffuse through the membrane quite easily. However, at pH 7 the grafted chains partially block the pores and the diffusional flux of bigger drug molecules (Mw 9400) decreases five orders of magnitude and also the flux of smaller molecules is clearly reduced. When the influence of the drug charge on the diffusion of the drugs across the membranes was studied, it turned out that the PAA-PVDF membranes facilitate the transport of cationic drugs and repel anionic ones. The presented mathematical model, based on Donnan equilibrium and measured transport number data, predicted the observed trends reasonably well.

Cantilever, three- and four-point bending methods used in the determination of intrinsic elasticity of pharmaceutical powders were evaluated with double-exposure holographic interferometry. Microcrystalline cellulose, dicalcium phosphate dihydrate and α-lactose monohydrate were compressed to rectangular beams and the bending measurements of samples captured on holographic images, which were evaluated by calculating the Young's modulus values for both the upper and lower surfaces of the samples. Several methods were used in the moduli calculations. It was found that the four-point bending method seemed to be best for determining results of the elasticity of soft pharmaceutical powders. The superiority of this method was due to the fact that it resulted in the most homogeneous bending along the beams. The results of the three-point bending method were, however, in good agreement with those of the four-point bending method. On the other hand, the cantilever method was observed to be unsuitable for pharmaceutical powders. Inspection of the holograms revealed that the integrity of α-lactose sample beams was inadequate for moduli evaluation. This would not have been noticed with conventional displacement measurements.

The optical surface quality of pharmaceutical tablets was investigated using a computer-generated hologram as a sensor. The optical surface quality was related to the porosity of the tablets.

The aim of this study was to evaluate the friction during double-sided tablet compression. Dicalcium phosphate dihydrate and lactose were tabletted with a compaction simulator with symmetrical and asymmetrical double-sided sawtooth punch displacement profiles. The estimation of force transmission in a powder column was based on an exponential equation, including the material parameter consisting of both the friction coefficient and Poisson's ratio. This parameter was predetermined from a single-sided compression. A novel equation was derived from a previously presented equation for friction work in single-sided tablet compression. The basic assumption was drawn from the linearly decreasing movement of infinitely thin particle layers, which are produced as the compressing punch surface approaches the other punch. This calculation was also based on the assumption that the equilibrium point, where the particles do not move, is halfway between the punches in the symmetrical profile and at a distance proportional to the amplitudes of the asymmetrical upper and lower sawtooth profiles. The tensile strength of tablets compressed with single-double-sided profiles was identical, and thus the behavior of the materials studied under compression was independent of the compression profiles. The friction work values that were calculated with the proposed expression for double-sided profiles were close to the theoretical values, as estimated by calculations based on compressions with single-sided profiles. In conclusion, the novel mathematical expression opens new possibilities for the evaluation of friction in double-sided compression; for example, in rotary press tabletting.

The particle and powder properties of α-,β-,γ- and hydroxypropyl-β- (HPβ) cyclodextrins (CDs) were examined. Special attention was paid to water interaction and thermal properties of CDs. The CDs studied showed big differences in particle size distribution and particle shape. In all cases, with the exception of βCD, the log-normal distribution described adequately the particle size distribution. However, the beta-distribution characterized well particle shape factor distribution. The typical α and β parameters obtained from the beta-distribution fitting are related to sphericity and shape uniformity of the particles. Water content results for CDs, obtained by loss on drying at 160°C and Karl Fisher methods, yielded similar results; thus, it was possible to evaporate practically all the water at 160°C. Water content of CDs ‘as received’ was dependent on the storage history of the samples after manufacturing. The DSC profiles of the CDs showed a broad, intense endothermic effect in the range 20–130°C, this asymmetric peak was ascribed to water removal. αCD showed a characteristic peak with an onset temperature 138°C. This peak seems to be independent of water content, and only small modifications are observed after drying at high temperature. Thus, a feasible structural change is associated with this peak.

The effect of the penetration enhancers Azone, 1-dodecanol, and dodecyl-2-(N,N-dimethylamino)propionate (DDAIP) on the structural integrity of liposomes composed of stratum corneum (SC) lipids was studied. With increasing enhancer concentration (0–1.5 mM) in the incubation medium (30% w/w aqueous ethanol), the lipid bilayer structure was found to become more disordered, as demonstrated by a decrease in 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescence anisotropy, and the efflux of the entrapped hydrophilic fluorescent marker, calcein, was found to increase. The lipid fluidizing effects of Azone and DDAIP were stronger than that of 1-dodecanol. In addition, transport of propranolol hydrochloride and sotalol hydrochloride, administered as solutions in 45% w/w aqueous ethanol containing 0–10 mM enhancer, was investigated across human epidermis in vitro. The flux enhancements of Azone and DDAIP were more pronounced with the hydrophilic sotalol and increased with increasing enhancer concentration, whereas 1-dodecanol was found to have a negligible effect. The flux of the lipophilic propranolol, on the other hand, was only slightly augmented by the enhancers. The lipid disordering effects and flux enhancement (especially that of the hydrophilic drug) followed a similar trend demonstrating the importance of SC lipid interactions as a mode of action of the enhancers studied.

Liposomes have been suggested as a vehicle for dermal and transdermal drug delivery, but the knowledge about the interaction between lipid vesicles and human skin is poor. Therefore, we visualized liposome penetration into the human skin by confocal laser scanning microscopy (CLSM) in vitro. Liposomes were prepared from phospholipids in different compositions and labeled with a fluorescent lipid bilayer marker, N-Rh-PE (L-alpha-phosphatidylethanolamine-N-lissamine rhodamine B sulfonyl). Fluorescently labelled liposomes were not able to penetrate into the granular layers of epidermis. However, the fluorescence from liposome compositions containing DOPE (dioleylphosphatidyl ethanolamine) was able to penetrate deeper into the stratum corneum than that from liposomes without DOPE. Pretreatment of skin with unlabeled liposomes containing DOPE or lyso-phosphatidyl choline (lyso-PC) enhanced the subsequent penetration of the fluorescent markers, N-Rh-PE and sulforhodamine B into the skin, suggesting possible enhancer activity, while most liposomes did not show such enhancement. Resonance energy transfer (RET) and calcein release assay between stratum corneum lipid liposomes (SCLLs) and the phospholipid vesicles suggested that the liposomes containing DOPE may fuse or mix with skin lipids in vitro and loosen the SCLL bilayers, respectively. Among the factors not affecting stratum corneum penetration were: negative charge, cholesterol inclusion and acyl chain length of the phospholipids. In conclusion, fusogenicity of the liposome composition appears to be a prerequisite for the skin penetration.

Double-exposure holographic interferometry was used to detect structural uniformity and bending properties of compressed rectangular beams consisting of microcrystalline cellulose, dicalcium phosphate dihydrate and α-lactose monohydrate. The fringes in holographic reconstructions produced a clear pattern for interpretation of bending without any complication. Thus, it was possible to calculate the elastic modulus values for both the upper and lower surfaces of the sample beams. The theoretical bending profiles versus experimental bending data were also evaluated. It was possible to detect unpredictable changes due, for example, to structural non-homogeneities and induced stress. The induced stress inside the beams had a slight effect on the ideal bending, due to the fixing of the beam. The modulus values obtained from extrapolation to zero porosity were in good agreement with the previously published results. According to this study, double-exposure holographic interferometry is a suitable, accurate and versatile method for mechanical studies of pharmaceutical powders and compacts.

The rate of release of indomethacin from ethylcellulose microcapsules prepared by coacervation was studied using internal buffer, dibasic sodium phosphate (DSP), to increase the solubility of the core. The dissolution rate of the drug was determined in phosphate buffer solutions of varying pH and concentration. The role of the stagnant diffusion layer at the microcapsule surface was also evaluated by changing the mixing in the dissolution test. Indomethacin release was accelerated considerably with increasing amounts of DSP in the core. DSP increases the pH inside the microcapsules, thus enhancing the release of the acidic drug. Increasing bulk solution pH increased the release rate of indomethacin, the enhancing effect being more pronounced with buffered microcapsules. Neither increasing phosphate concentration of the bulk solution nor increasing mixing of the microcapsules influenced the rate of release of indomethacin from unbuffered capsules. With buffered capsules the increase in phosphate concentration of bulk solution prevented leaching out of internal phosphate increasing the release rate of indomethacin. The release of indomethacin also accelerated slightly with increasing mixing.

A nondestructive method based on pulse photoacoustics was applied for evaluation of elasticity and integrity of pharmaceutical tablets. Variations in porosity, density and sodium chloride content of microcrystalline cellulose tablets were found to be related to parameters extracted from the through-transmitted ultrasonic wave forms. By using the amplitudes and ultrasonic velocities of these wave forms, it was possible to obtain values of a transverse to longitudinal amplitude ratio, and also elastic parameters, such as Young's and shear moduli, for the tablets. Poisson's ratio was calculated from the elastic moduli as well as from the amplitudes. An exponential relationship between tablet porosity and the attenuation of longitudinal wave form was noticed. The transverse to longitudinal amplitude ratio and the amplitudinal Poisson's ratio were indicative of structural variations, e.g., changes in the porosity and the sodium chloride content of tablets. Young's and shear moduli of microcrystalline cellulose tablets were found to follow similar porosity trends to those in previously published beam bending and twisting studies, although the absolute values and the values extrapolated to zero porosity were slightly smaller. The Poisson's ratio calculated from the experimental Young's and shear modulus values was also in agreement with earlier studies, but the values extrapolated to zero porosity differed significantly. The method is a promising tool for evaluating the elastic properties of tableting materials and the structural variations in tablets.

Purpose. Thermophysical properties of three tableting excipients; microcrystalline cellulose, lactose and dicalcium phosphate dihydrate were observed to evaluate their ability to resist temperature induced changes in tablet form.

The effects of mechanical treatment and various storage conditions on the structure of cyclophosphamide monohydrate were evaluated by thermal and X-ray analyses and molecular modeling. The monohydrate form of cyclophosphamide was found to convert to the anhydrous form through a metastable phase. Metastable forms were produced by mechanical treatment and by desiccation. These forms could be detected in differential scanning calometric thermograms as endothermic peaks, at approximately 39°C, and X-ray powder diffractometric analysis, e.g.; by a characteristic reflection at 15.3° (2θ). Molecular modeling was used to study molecular interactions and putative metastable structures. The dehydration enthalpies of the cyclophosphamide monohydrate obtained from quantum chemical calculations and DSC analysis were 51.6 and 36.1 J/g, respectively. In a unit cell of the stable monohydrate, a water molecule is held by O(7) of the cyclophosphamide molecule and N(6)H of a neighboring cyclophosphamide molecule, with hydrogen bonds enabling existence of a water tunnel. The metastable form of cyclophosphamide is detected when a sterically formed block in the possible tunnel is removed, and the water molecules are allowed to leave the system one by one.

Several types of controlled drug release microspheres has been developed. In this study, we describe a new type of microspheres that control drug release with changing inner core pH. In the microspheres, micronized model drug, timolol maleate and pH-adjusting agents (mono, di, and trisodium phosphate or Tris buffer) were either dry blended by mixing or coprecipitated by spray drying, and encapsulated in X7-3012 silicone microspheres using emulsion vulcanization technique. Upon water influx into microspheres, buffer dissolves and adjusts the inner pH. Thus, the fraction of unionized drug is increased by higher pH and, consequently, partition-driven release of basic drug from the microspheres is accelerated. Scanning electron micrographs showed that spray dried materials were completely encapsulated by the elastomer, and the drug was homogenously distributed in silicone micromatrices. An amine resistant silicone elastomer could be used to make microspheres incorporating up to 30 wt% of solid particles. Typical size range of the pH-controlled microspheres was 150–200 μm. Timolol release from the microspheres followed square root of time kinetics, and it was proportional to wt% loading level of drug in the micromatrices. In vitro release of timolol from microspheres can be controlled over a wide range of rates by selecting a suitable pH adjusting agent and by varying its amount in the microspheres. Spray drying of the drug and buffer together was the most effective in controlling the drug release since, in this case, buffer was in the same microcompartment inside silicone and thus buffering effect was maximal. Drug release from pH-controlled microspheres was independent of pH of dissolution medium.

The effect of the penetration enhancers Azone, oleic acid, 1-dodecanol, dodecyl N,N-dimethylaminoacetate (DDAA), and dodecyl N,N-dimethylaminoisopropionate (DDAIP) on epithelial membrane lipids was examined using human buccal cell membranes as a model for epithelial lipid bilayer. Buccal epithelial cells (BEC) were labeled with l,6-diphenyl-l,3,5-hexatriene (DPH), l-(4-(trimethylammonio)phenyl)-6-phenyl-l,3,5-hexatriene (TMA-DPH), and 8-anilino-l-naphthalene sulphonic acid (ANS) fluorophores to characterize enhancer-induced changes in the hydrophobic core, in the superficial polar head region, and on the exterior surface, respectively, with fluorescence anisotropy and fluorescence lifetimes. All the enhancers studied were found to decrease the BEC membrane lipid packing order in a concentration-dependent and time-dependent manner in the deep bilayer region, as shown by a 37–66% decrease in anisotropy. Oleic acid was also found to disrupt membrane lipids strongly in the polar head region, causing at least a 34% decrease in anisotropy values. Azone and DDAA were shown to alter molecular movement on the surface of the bilayers (24 and 19% decrease in anisotropy, respectively). The results suggest that interaction with membrane lipid domains is an important, but not the only, mode of action for the penetration enhancers studied.

Irritation of the skin by chemical penetration enhancers may limit the use of these compounds in transdermal drug delivery. Biodegradable enhancers like dodecyl N , N -dimethylamino acetate (DDAA) have been synthesized previously to decrease the duration of action and toxicity of the enhancers. We studied the reversibility and extent of penetration enhancement and skin irritation by DDAA, Azone, and n -dodecanol in rabbit pinna skin using timolol and propranolol as penetrants. Also, in vitro and in vivo permeabilities of the drugs with and without enhancers were compared. Drug concentrations in diffusion chambers and rabbit plasma were determined using HPLC and radio receptor assay, respectively. Skin irritation was measured with a chromameter. DDAA and Azone caused approximately equal transdermal penetration enhancement of model drugs in vitro but the potency of n -dodecanol was lower. In vivo, Azone was the most irritating enhancer in rabbit pinna skin. Both enhancer effects and skin irritation by DDAA were reversed in 4 days, while the effects of Azone and n -dodecanol lasted longer. Thus, it is possible to affect the duration of skin alteration by enhancer design. Propranolol was more irridating than timolol in rabbit pinna skin in vivo. Percutaneous permeability of propranolol in vivo, calculated from pharmacokinetic parameters, was considerably greater than its in vitro permeability coefficient. In contrast, in vitro and in vivo permeability coefficients of timolol were comparable. The increased permeation of propranolol in vivo may be due to skin irritation, because in vivo permeability coefficients correlated with associated skin irritation.

In this study the deposition and gastrointestinal transit of a conventional uncoated tablet, a chewable tablet, as well as an effervescent preparation containing 1 g of 99m Tc-labelled sucralfate were evaluated over 180 min using a gamma camera. Each preparation was administered by five healthy volunteers after 10 h fasting. The conventional tablet and the effervescent preparation seemed to distribute immediately in the whole stomach area. With the chewable tablet, the initial deposition of sucralfate in the mouth and oesophagus was also detected. The transit of sucralfate into the intestinal area was noted for the conventional tablet and for the effervescent preparation as early as after 10 min, whereas the increase in sucralfate concentration in the intestinal area after administration of chewable tablets was observed after 30 min. After 60 min the amount of sucralfate remaining in the stomach was about 40% for the conventional tablet, about 20% for the effervescent preparation and about 80% for the chewable tablet. Thus, the effervescent preparation of sucralfate, administered as a suspension, was transported more rapidly into the intestine than the solid oral dosage forms. After 180 min almost all of the sucralfate liberated from the conventional and effervescent formulations was transported from the stomach into the intestine, whereas 21% of that liberated from chewable tablets was still present in the stomach. The dosage form of sucralfate seemed to have a significant effect on the gastrointestinal distribution and transit of sucralfate.

The compression behaviour of plastically flowing microcrystalline cellulose and pregelatinized corn starch and fragmenting α-lactose monohydrate and dicalcium phosphate dihydrate, and their binary mixtures was evaluated using the Heckel equation. Powders were compressed using an instrumented eccentric tablet press. The Heckel plots for both plastically flowing materials and their binary mixtures were linear in shape. In contrast, on the Heckel plots of the fragmenting materials and their mixtures, an obvious curvature was seen. The mean yield pressures were linearly proportional to the mixture composition of two plastically flowing materials. When mixed with a fragmenting material, a plastically flowing component had a greater effect on the compression behaviour of the mixture than a fragmenting mixture component had. This was explained by the more pronounced effect of plastic flow on volume reduction. When two fragmenting materials were compressed, the densification of their binary mixture was strongly influenced by the less compressible material with higher mean yield pressure. It was concluded that in the mixtures of two fragmenting materials the particles of the less compressible material constituted a firm structure, like a skeleton, which tended to dominate the compression behaviour of the binary mixtures. For binary mixtures of fragmenting materials the mean yield pressures were thus not linearly proportional to the mixture composition. Compression behaviour of powder mixtures seemed to be strongly dependent on the deformation properties of plain materials to be compressed. On the other hand, one mixture component may dominate the compression behaviour of the mixture, and the compressibility may change non-linearly with mixture composition. Therefore, caution is needed when the Heckel equation is applied for predicting compression behaviour of powder mixtures.

The extent of the polymorphic transformation of anhydrous caffeine has been studied as a function of grinding time and compression pressure by using quantitative X-ray diffraction analysis. The measurements show that both grinding and compression induce the transformation from the metastable form I into the stable form II. The transformation can be observed even after 1 min grinding or by using a compression pressure of about 50 MPa in tableting. The degree of transformation is greater near the surface than in the middle part of the tablet.

To observe the rise in temperature during tabletting an infrared thermoviewer was used together with an instrumented eccentric tablet press. To evaluate the tabletting process, temperatures measured from surfaces of recently ejected tablets were used together with energy parameters. Two direct compression excipients, plastically deforming microcrystalline cellulose and fragmenting dicalcium phosphate dihydrate, were tabletted. Due to differences in specific heat values, the temperature rise of the tablets was higher with microcrystalline cellulose than with dicalcium phosphate. Also more non-homogeneous particle shape and plastic deformation instead of fragmentation may have led to higher temperatures of microcrystalline cellulose tablets. For both test materials the temperature of the tablets rose with the compressional force whereas lubrication diminished the rise in temperature. Due to the non-homogeneous densification the highest temperature values were obtained at the centre of the upper surfaces of the tablets. After a short initial stabilization phase, the rise in tablet temperature became greatly dependent on the temperature increase of the powder in the hopper. From the energy parameter values, derived either from force and displacement data (mechanical energy), or from specific heat, temperature increase and tablet weight values (thermal energy), it was noted that the mechanical energy was very extensively converted to thermal energy. Thus, a permanent increase in energy content of powders by compression seemed to be small. The infrared thermoviewer was found to be an accurate and informative method for evaluating changes in the temperature and energy content of compressed powders during a dynamic tabletting process.

The effectiveness of a new biodegradable penetration enhancer, dodecyl N, N-dimethylamino isopropionate (DDAIP) was compared to dodecyl N,N-dimethylamino acetate (DDAA), another biodegradable penetration enhancer, and to Azone®, lauryl alcohol (LA), and oleic acid (OA) in vitro using shed snake skin in modified Franz-type diffusion cells. 5-Fluorouracil (5FU), a hydrophilic drug with poor skin permeability, was used as a model permeant. Skin samples were pretreated with pure liquid enhancers. 5FU flux through the control and enhancer treated skin increased linearly with its concentration in the donor compartment. DDAIP and DDAA interacted with the skin rapidly ( 40-fold) with the dose of DDAIP up to 10 μ1. Thereafter the flux did not increase significantly. With DDAA no plateau effect was observed with the applied volumes up to 50 μ1. Skin pretreatment with 5 μ1 of DDAIP, DDAA, Azone®, LA, and OA increased the permeability of 5FU 69-, 24-, 23-, 5-, and 2-times, respectively. Substitution of a methyl group for a hydrogen atom in the acetate moiety of DDAA was observed to markedly increase transdermal penetration enhancement.

The effect of aqueous dissolution medium properties on the release of model drug, propranolol, from water-activated and pH-controIled devices was investigated in vitro in diffusion cells. In the devices, powders of propranolol hydrochloride and pH-adjusting adjuvant, disodium phosphate, were entrapped between two silicone membranes. pH of dissolution medium ranged from 1.6 to 9.4, osmotic pressure from 138 to 950 mOsm/kg and ionic strength was 0.15 or 0.3. The osmolality and ionic strength of dissolution medium affected neither the inner pH and water content in the device nor the release of propranolol from the devices. When pH in the dissolution medium was raised, the inner pH of the device was increased slightly but not adequately to change propranolol release. Thus, the release of propranolol from the tested silicone reservoir devices was essentially independent of its environment.

Indomethacin was microencapsulated in a coacervation process using ethylcellulose as a wall material and polyisobutylene as a coacervation inducing agent. Micronized sodium chloride was added as a pore former into the microcapsule wall. Microcapsules were tabletted with plastically deforming microcrystalline cellulose and fragmenting dicalcium phosphate as well as with their binary mixture. The effect of compression pressure on drug release was evaluated. The release of indomethacin was also studied after effective disintegration of the tablets by crosslinked sodium carboxymethylcellulose. Release of indomethacin from plain microcapsules accelerated markedly when sodium chloride was added in the microcapsule wall. All the tablets without disintegrant stayed nearly intact during the dissolution test. The tablets of microcapsules were composed of a porous ethylcellulose matrix in which the microcapsules were separated from each other by easily wettable tablet adjuvants. The drug release accelerated from the tablets due to the mechanical destruction of microcapsule wall, which was more clearly seen after disintegration of the tablets to the multiple microcapsule units. The rupture of microcapsule films was most extensive with the tablets containing fragmenting dicalcium phosphate as a filler. The addition of sodium chloride in the microcapsule wall seemed to make the polymer film firmer thus reducing the destructive effect of tablet adjuvants.

The electrochemical properties of human cadaver skin were studied in a diffusion cell with impedance spectroscopy as a function of time in the absence and presence of penetration enhancers dodecyl N,N-dimethylamino acetate and Azone. An improved electrochemical model of skin is presented, and combining the novel model with modern fractal mathematics, the effect of enhancers on the surface of skin is demonstrated. The enhancers appeared to open new penetration routes and increase the ohmic resistance, capacitive properties, and fractal dimension of skin, which means a rougher or more heterogeneous surface.

Microcapsules of indomethacin and ascorbic acid were prepared by phase separation of ethylcellulose from cyclohexane using polyisobutylene as a coacervation inducing agent. Different amounts of solid sodium chloride were added to the microcapsule wall in order to alter the porosity of the film and hence to enhance the release of the core materials. The microcapsules prepared were matrix type, coacervates of many drug particles and ethylcellulose. The release of the poorly water-soluble indomethacin was found to be very slow from the ethylcellulose microcapsules, but it was accelerated considerably with increasing amounts of sodium chloride. Indomethacin released through the pores formed when sodium chloride dissolved from the microcapsule film. The release was controlled by the solubility of the weakly acidic drug. Thus a good linearity for the release data was obtained with the Hixson-Crowell cube-root law. The release of the water-soluble ascorbic acid from matrix-type microcapsules was observed to be incomplete and strongly dependent on the core/wall ratio of the microcapsules. The release of ascorbic acid accelerated in some degree as a function of sodium chloride from the microcapsules of higher core to wall ratio, but the enhancement in drug release was quite minimal with the thicker walled ones. Sodium chloride particles acted as pore formers only at the surface of the inhomogeneous microcapsule matrices. The release of the drug was considered to be diffusion controlled having a biphasic release profile against the square root of time.

Microspheres of disodium cromoglycate (DSCG) were prepared with either polyacrylic acid (Carbopol 934) or sodium carboxymethylcellulose (NaCMC) by the spray-drying technique. The arithmetic mean diameter of the spraydried particles ranged from 3.2 to 5.7 microns. The plain DSCG particles and the microspheres containing NaCMC were spherical and had a smooth surface, whereas the microspheres containing Carbopol 934 were more irregular and partly shrunken. The dissolution rate of the plain DSCG was prolonged when the drug was incorporated with the polymers. The more polymer the microspheres contained the slower the drug release rate. The in vitro mucoadhesion test showed that the plain DSCG was nearly as mucoadhesive as the the plain polymers. The microspheres of DSCG with either of the polymers were, however, clearly more mucoadhesive than the plain starting materials. The adsorption isotherms showed the hygroscopic nature of the polymers and DSCG. The hydration of the microspheres increased as a fu...

The pharmacokinetics of two 200 mg ibuprofen (IP) film-coated tablets and a 200 mg effervescent tablet were studied in cross-over fashion on 14 healthy volunteers. After ingestion of the novel film-coated tablet, absorption half life (0.6 h) was 42-50 % (p

99m Tc-labelled disodium cromoglycate particles and 111 In-labelled microspheres of disodium cromoglycate and polyacrylic acid were administered simultaneously to the nasal cavities of four healthy volunteers. The initial deposition patterns of the inhaled powder mixture as well as the drug removal due to the mucociliary clearance were monitored by a gamma camera. The double-labelling technique enabled in vivo comparison of simultaneously administered plain drug particles and polyacrylic acid microspheres of disodium cromoglycate. After administration, both the plain drug particles and the microspheres distributed equally effectively. On average, 27% of the 99m Tc-labelled plain drug particles and 50% of the 111 In-labelled microspheres were retained at the initial site of deposition 30 min after inhalation. Thus, the removal of microspheres from the nasal cavities was clearly impeded by polyacrylic acid.

The effectiveness of the penetration enhancers, dodecyl N,N-dimethylamino acetate (DDAA) and Azone, on pretreated human epidermis for the permeation of model drugs, indomethacin, 5-fluorouracil, and propranolol-HCl, was studied in in vitro diffusion cells. Snakeskin (Elaphe obsoleta) and rabbit pinna skin were compared as possible models for human skin. The drug concentrations were analyzed by HPLC. With all skins and all model drugs, DDAA increased drug permeability at least as well as Azone, and in most cases it was a more effective permeation enhancer. The relative permeation improvements in human skin, snakeskin, and rabbit skin were 10- to 20-, 5- to 50-, and 20- to 120-fold, respectively. Tritiated water served as an indicator of skin condition. Its penetration in the skin samples was independent of the drugs used, and both penetration enhancers significantly increased the flux of tritiated water through all skins. Thus, DDAA and Azone significantly increased the permeation of lipophilic and hydrophilic model compounds. Rabbit pinna skin was a poor model for human skin in vitro, while snakeskin was much closer to human skin in terms of transdermal permeability. In most cases drug permeability decreased in the order rabbit much greater than human greater than or less than snake.

Deposition of 99m Tc-labelled particles of disodium cromoglycate in the human respiratory tract after inhalation either from the conventional metered dose aerosol or from the new Ingelheim powder inhaler (FO II) was compared. Fractional deposition in the whole lung area, in the upper airways and in the device was measured using a gamma camera. Eight healthy informed volunteers participated in the inhalation test. The lung deposition of the inhaled drug was about 9% using the conventional aerosol actuator with the short plastic mouthpiece whereas, using the Ingelheim powder inhaler, on average 20% deposition in the whole lung area was achieved. In addition, with the Ingelheim inhaler drug particles seemed to be deposited in the more peripheral parts of the respiratory tract. The upper airway deposition was also reduced with the Ingelheim powder inhaler. On the other hand, a larger fraction of the drug dose was retained in the Ingelheim inhaler than in the aerosol actuator.

The inherent material properties of four cellulose powers were evaluated and the effect of these properties on the mechnical strenght and surface hardness of direct compression tablest was studied. Two of the materials studied were the other two were experimental cellulose powers, and agglomerated cellulose and a deploymerized cellulose.The agglomerated cellulose powder formed the strongest as well as the hardest tablets. Also both microcrystalline celluloses formed clearly stronger tablets than depolymerized cellulose, but surface hardness of the tablets compressed using these three cellulose powders was, however, quits similar.The most important material property affecting the breaking strength of tablets was the suesific surface area of the starting material. No correlaiton between cystallinity, particle size or particule shape starting material and the strength of tablets was observed.The surface hardness of tablets showed no simple correlation with the breaking strenth of tablets or with any ...

Three methods for modeling and predicting water contact angle for a heterogeneous series of pharmaceuticals using computed molecular descriptors and statistical analysis were developed. A number of theoretical molecular descriptors that were related to the structure and physicochemical properties were computed for compounds (n=34) whose experimental water contact angle was known. Thereafter, the descriptors were subjected to partial least squares projections to latent structures analysis. Three multivariate models were derived that allowed theoretical prediction of water contact angle for structurally heterogeneous materials. The R2 and Q2 values of the models ranged from 0.57 to 0.80 and 0.42 to 0.66, respectively. The models had moderate predictive ability and provided useful information about the molecular and physicochemical properties that affect material water contact angle. Increases in the bulkiness and hydrophobic molecular surface area of a molecule increased material water contact angle, whereas the greater presence of hydrophilic surfaces, which are not capable for hydrogen bonding, decrease materials water contact angle. Water contact angle can be predicted well for pharmaceutical solids using theoretical molecular descriptors that reflect the interaction potential of crystal/particle surfaces with water.

Earlies studies suggest that solution calorimetry can be used to determine the extent of amorphous content of drug and excipient, when the solubility and dissolution rate of the compound in the chosen solvent are reasonably high. In the present study, the use of solution calorimetry for assessment of amorphous content of a sample that is not completely dissolved in a solvent was evaluated. Physical mixtures of lactose and spray-dried lactose samples were analysed. The amorphous content of the physical mixtures and the spray-dried samples varied from 0% to 100% determined by isothermal microcalorimetry. The enthalpy of solution (delta(sol)H) was determined in water. The lactose samples were dissolved quickly in water. In addition, the enthalpy accompanied with an addition of a lactose sample in an over saturated aqueous solution (delta(sat)H) (prepared from the corresponding lactose sample) was determined. The lactose sample did not completely dissolve in the over saturated aqueous solution. An excellent correlation was observed between delta(sol)H and the amorphous content of the samples. Interestingly, there was a linear correlation also between delta(sat)H and the amorphous content of the samples. Further, a linear relationship was observed between the delta(sat)H and the delta(sol)H of the samples. Therefore, solution calorimetry may represent a rapid and simple method for determining the amorphous content also in samples that are not completely dissolved in the solvent.