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At least 973 records · Page 54Linked to original sources
PubMed1999

5'-hydroxycotinine-N-oxide, a new nicotine metabolite isolated from rat urine.

1. 5'-Hydroxycotinine-N-oxide, 5-(3-pyridyl-N-oxide)-5-hydroxy-1-methyl-pyrrolidone-2, was identified as a new in vivo metabolite of nicotine. 2. The new metabolite was isolated from the urine of rats treated with S-nicotine and characterized using chemical and spectrometric methods. 3. 5'-Hydroxycotinine-N-oxide was synthesized and characterized by MS and by infrared as well as 1H- and 13C-NMR spectroscopy. 4. Identity of the new metabolite with synthetic 5'-hydroxycotinine-N-oxide was demonstrated by comparing the MS and 1H-NMR spectroscopy data as well as by co-chromatography of a spiked urine sample.

Animals↗
PubMedDate not supplied

Characterization of protein-loaded poly(epsilon-caprolactone) microparticles based on a factorial design.

This study was designed to systematically investigate the characteristics of bovine serum albumin (BSA) loaded poly(epsilon-caprolactine) (PCL) microparticles based on a 2(4) factorial experiment. The influences of polyvinyl pyrrolidone (PVP) concentration, BSA/PCL ratio, w/o/o/o ratio, and PEG/PCL ratio on the surface morphology, particle size, as well as the yield of microparticles, encapsulation efficiency of BSA, and in vitro release properties were evaluated. The microparticles were prepared by the w/o/o/o solvent evaporation method. The structure of BSA retained its integrity using this technique. The mean particle sizes of BSA-loded microparticles were in the range of 20-50 microm, and a highly porous morphology existed in these microparticles, irrespective of the formulations. The production yields of microparticles were in the range of 52.1-89.0%, and the encapsulation efficiencies were in the range of 13.8-68.3%. The burst release of BSA was in the range of 6.9-69.0%. The volume ration of the multi-phases significantly affected the encapsulation efficiency of BSA in PCL microparticles, and the initial amount of BSA encapsulated by PCL in terms of BSA/PCL ratio significantly affected the amount of BSA released at the end of 14 days (p < 0.05).

Analysis of Variance↗
PubMedDate not supplied

Protective colloids and polylactic acid co-affecting the polymorphic crystal forms and crystallinity of indomethacin encapsulated in microspheres.

The co-effect of protective colloids and polylactic acid (PLA) on the polymorphic crystal forms and crystallinity of indomethacin (IMC) in IMC-loaded PLA microspheres was investigated with differential scanning calorimetry, infrared spectroscopy and x-ray diffractometry, to evaluate the polymorphic crystal forms and crystallinity of IMC encapsulated in PLA microspheres. The surfactant, sodium dodecyl sulphate (SDS), was also used as a dispersing agent. The results indicate that the polymorphism and crystallinity of IMC encapsulated in IMC-loaded PLA microspheres was dependent on the type of protective colloid and PLA used. The amorphous state and alpha-form of IMC were found in the IMC-loaded PLA microspheres prepared using polysaccharide (pectin or beta-cyclodextrin) as a protective colloid or SDS as a dispersing agent. However, the amorphous and methylene chloride solvate of IMC seemed to exist in the IMC-loaded PLA microspheres prepared with the proteins (gelatin or albumin), synthetic cellulose derivative (methyl cellulose or hydroxylpropyl methylcellulose) or the synthetic nonionic polymer (polyvinyl alcohol, polyvinyl pyrrolidone or biosoluble polymer) as a protective colloid. PLA was found to express a certain crystallinity in microspheres and not be affected by the protective colloids, but it played a more important role in influencing the crystallization of IMC during microencapsulation than the protective colloids. No interaction occurred in the physical mixture of IMC and PLA, nor in the IMC-loaded PLA microspheres.

Calorimetry, Differential Scanning↗
PubMedDate not supplied

Effect of protective colloids on the induction of polymorphic changes in indomethacin agglomerates after solvent evaporation from o/w emulsions.

Indomethacin (IMC) agglomerates were prepared by the solvent evaporation process from o/w emulsions containing different protective colloids in the external aqueous solution. The types of protective colloids inducing the polymorphic transformation of IMC in the agglomerates without wall material were investigated. The composition and its polymorphs were evaluated from the X-ray diffraction patterns, IR spectra and DSC thermograms. The results indicate that when pectin, beta-cyclodextrin, sodium alginate or sodium dodecyl supphase acted as a protective colloid, the respective IMC agglomerates consisted only of the alpha form of IMC. When gelatin or hydroxypropyl methylcellulose was used as a protective colloid, the amorphous, alpha and gamma forms as well as methylene chloride solvates of IMC were found in the IMC agglomerates. There was only methylene chloride solvate of IMC with a small amount of amorphous form in the IMC agglomerates prepared from albumin as a protective colloid, while IMC agglomerates prepared from methylcellulose, polyvinyl alcohol or biosoluble polymer consisted of the mixture of amorphous and alpha forms, and methylene chloride solvate of IMC. When polyvinyl pyrrolidone was applied to act as a protective colloid, the mixture of methylene chloride solvate and gamma form of IMC with less quantity of amorphous form was found in its IMC agglomerates. This strongly suggests that the composition of IMC agglomerates prepared from the solvent evaporation process was significantly influenced by the type of protective colloids used.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

The biophysics of the gram-negative periplasmic space.

When subject to an osmotic 'up-shock', water flows outward from bacterial cytoplasm of the bacterium. Lipid bilayers can shrink very little in area and therefore must wrinkle to accommodate the smaller volume. The usual consequence is that all the layers of the cell envelope must become wrinkled together because they adhere to each other and must now cover a smaller surface. Plasmolysis spaces are formed if the cytoplasmic membrane (CM) separates from the other components of the wall. However, because the CM bilayer is essentially an incompressible two-dimensional liquid, this constraint restricts the location and shape of plasmolysis spaces. With mild up-shocks they form at the pole and around constricting regions in the cell. Elsewhere their creation requires the formation of endocytotic or exocytotic vesicles. The formation of endocytotic vesicles occurs in animal and plant cells as well as in bacterial cells. With stronger up-shocks tubular structures (Bayer adhesion sites), or other special geometric shapes (e.g., Scheie structures) allow the bilayer to surround an irregular shaped cytoplast. Periosmotic agents, that is, those that extract water from the periplasm as well as the cytoplasm, are molecules such as poly-vinyl-pyrrolidone and alpha-cyclodextrin that are too large to pass through the porins in the outer membrane. They were found to significantly inhibit the formation of plasmolysis spaces. Presumably, they inhibit the plasmolysis process, which requires that extracellular fluid enter between the CM and the outer membrane (OM). In the extreme case, with the dehydrating action of both osmotic agents and periosmotic agents, periplasmic space formation tends to be prevented and a new kind of space develops within the cytoplasm. We have designated these as 'cytoplasmic voids'. These novel structures are not bounded by lipid bilayers, in contrast to the endocytotic vesicles. These new spaces appear to result from the negative turgor pressure generated by the application of the combination of osmotic and periosmotic agents causing bubble formation. Several ideas in the literature about the wall biology (periseptal annuli, leading edge, osmotic pressure in the periplasm) are presented and critiqued. The basic criticism of these is that much of the phenomena can be explained because of the physics of the phospholipid bilayers and osmotic forces and thus does not imply the existence of a special control mechanism to regulate growth and division.

Biophysical Phenomena↗
PubMed2004

An analysis of candidates for addition to the Clean Air Act list of hazardous air pollutants.

There are 188 air toxics listed as hazardous air pollutants (HAPs) in the Clean Air Act (CAA), based on their potential to adversely impact public health. This paper presents several analyses performed to screen potential candidates for addition to the HAPs list. We analyzed 1086 HAPs and potential HAPs, including chemicals regulated by the state of California or with emissions reported to the Toxics Release Inventory (TRI). HAPs and potential HAPs were ranked by their emissions to air, and by toxicity-weighted (tox-wtd) emissions for cancer and noncancer, using emissions information from the TRI and toxicity information from state and federal agencies. Separate consideration was given for persistent, bioaccumulative toxins (PBTs), reproductive or developmental toxins, and chemicals under evaluation for regulation as toxic air contaminants in California. Forty-four pollutants were identified as candidate HAPs based on three ranking analyses and whether they were a PBT or a reproductive or developmental toxin. Of these, nine qualified in two or three different rankings (ammonia [NH3], copper [Cu], Cu compounds, nitric acid [HNO3], N-methyl-2-pyrrolidone, sulfuric acid [H2SO4], vanadium [V] compounds, zinc [Zn], and Zn compounds). This analysis suggests further evaluation of several pollutants for possible addition to the CAA list of HAPs.

Air Pollutants↗
PubMed2002

Transfollicular drug delivery: penetration of drugs through human scalp skin and comparison of penetration between scalp and abdominal skins in vitro.

In order to quantitatively investigate the importance of transfollicular pathway for drug delivery, drug penetration through human scalp skin was investigated using liquid formulations containing lipophilic and hydrophilic drugs in vitro. The penetration pathway for drugs through the scalp skin was examined using fluorescent probes. Additionally, the drug penetration through the scalp skin was compared with that via human abdominal skin to clarify the usefulness of intrafollicular delivery. Lipophilic melatonin (MT) and ketoprofen (KP) showed high permeabilities through the scalp skin, although the flux of KP was much higher. Absorption enhancers, N-methyl-2-pyrrolidone and isopropylmyristate, only slightly increased the fluxes. Hydrophilic fluorouracil (5FU) and acyclovir (ACV) penetrated through the scalp skin with relatively large fluxes. However, there was large variability in the fluxes of these drugs across scalp skin from different sources. When the relationship between the flux and hair follicle density was estimated, there was good correlation between the two (r = 0.651 for MT and r = 0.666 for ACV, P < 0.05). The histologic examination of the scalp skin, following application of the formulation with nile red or sodium fluorescein, indicated that the probes permeated into the junction of the internal and external root sheath of follicles and diffused into the dermis via the outer root sheath at the initial times. The penetration of nile red, a lipophilic probe, via the stratum corneum of scalp skin was later than that via the follicles. The permeation of MT and 5FU through the scalp skin was much higher than that via the abdominal skin, being 27 and 48 times as high as the abdominal skin, respectively. These results indicate that the drug delivery through the scalp skin will offer an available delivery means for drugs, particularly for hydrophilic drugs.

Abdomen↗
PubMed2002

Optimizing pH-responsive polymeric micelles for drug delivery in a cancer photodynamic therapy model.

Different pH-sensitive, randomly- and terminally-alkylated N-isopropylacrylamide (NIPAM) copolymers were synthesized and used to prepare pH-responsive polymeric micelles (PM). These copolymers were modified from previously-studied copolymers by incorporating an additional hydrophilic monomer, N-vinyl-2-pyrrolidone (VP) to decrease uptake by the mononuclear phagocyte system (MPS) and improve localization in tumors. VP lowered the phase transition pH of the copolymers but did not affect the onset of micellization. The in vitro cytotoxicity of the copolymers was evaluated on EMT-6 mouse mammary tumor cells in comparison to Cremophor EL (CRM). The anticancer photosensitizer aluminum chloride phthalocyanine (AlClPc) was loaded into the PM with a standard dialysis procedure. Biodistribution and in vivo photodynamic activity were then evaluated in Balb/c mice bearing intradermal EMT-6 tumors. All NIPAM copolymers demonstrated substantially lower cell cytotoxicity than the control surfactant CRM. In vivo, similar AlClPc tumor uptake was observed for the PM and CRM formulations. However, the PM appeared to exhibit greater activity in vivo than CRM formulation at an AlClPc subtherapeutic dose. Therefore, NIPAM-based copolymers containing VP units represent promising alternatives for the formulation of poorly water-soluble phthalocyanines.

Animals↗
PubMed2005

Targeted delivery of arjunglucoside I using surface hydrophilic and hydrophobic nanocarriers to combat experimental leishmaniasis.

The purpose of the present study was to investigate the therapeutic efficacy of the indigenous drug arjunglucoside I (AG) against in vivo models of experimental leishmaniasis by incorporating it in surface hydrophilic co-polymeric nanogel particles of size less than 100 nm diameter and to compare its efficacy with that of the free drug as well as the drug encapsulated in hydrophobic poly-dl-lactide (PLA) nanoparticles. The drug AG, having glucose at the terminal end of the glycosidic chain, was isolated from an indigenous source. Drug-incorporated ultra-low-sized nanogels (approximately 90 nm in diameter) composed of cross-linked random co-polymer of N-isopropylacrylamide (NIPAAM) and N-vinyl pyrrolidone(VP) were prepared, characterized and used as delivery vehicles to combat experimental leishmaniasis in hamster models. For comparison, drug-encapsulated hydrophobic nanoparticles (approximately 250 nm in diameter) made from PLA were used as a control. The drug AG was incorporated in these nanocarriers and these drug-nanocarrier complexes were physically characterized. The efficacy of lowering spleen parasite load by the free drug, as well as that incorporated in nanogels and PLA nanoparticles were examined in vivo in equimolar concentration against hamsters undergoing experimental leishmaniasis. The reduction of drug toxicity by the nanogels and PLA nanoparticles was also assessed. The efficacy in the lowering of spleen parasite load with the free drug was found to be only 38% but was much higher when the drug was incorporated in co-polymeric nanogels (79%) or in polymeric nanoparticles (75%). Both the nanocarriers were found to be effective in reducing hepatotoxicity and nephrotoxicity nearly to the same extent. It was apparent that in addition to a smaller size and better drug release profile, the contribution of other parameters, e.g. overall surface hydrophilicity or hydrophobicity of the vehicles, also play an important role in the macrophage uptake of the drug. However, whatever be the exact mechanism, being highly efficient, non-hepatotoxic and non-nephrotoxic, AG in either of the two nanoparticulate forms may have useful application in humans

Animals↗
PubMedDate not supplied

Development of matrix-membrane transdermal drug delivery system for atenolol.

A polymer matrix system for transdermal delivery of Atenolol was developed for its prolonged and controlled release systemic availability. To achieve the desired and controlled release rate, different combinations of Eudragit RL with polyvinyl pyrrolidone and polyethylene glycol 4000 were used in the preparations of polymeric matrix system. These preparations were evaluated for in vitro release and permeation of the drug across pig skin. The desired systems exhibited linear relationship between drug release (Q) versus ne0.8(hr0.8). The product exhibiting required skin permeation 64 mcg/h/cm2 to achieve an effective plasma concentration was selected for the in vivo performance evaluation. The drug plasma profile was compared with the plasma profile obtained following the administration of a conventional oral dose of Atenolol. The study revealed that the designed polymeric matrix transdermal drug delivery system of Atenolol could be successful with improved performance.

Administration, Cutaneous↗
PubMedDate not supplied

Evaluation of polyvinyl acetate dispersion as a sustained release polymer for tablets.

Kollicoat SR 30D is a unique 30% aqueous dispersion of polyvinvyl acetate stabilized by polyvinyl-pyrrolidone intended for preparation of sustained release products. Detailed evaluation of this polymer dispersion as a sustained release coating for active pharmaceutical ingredients of two diverse classes of drugs was studied. A water insoluble drug (ibuprofen) and a water soluble drug (ascorbic acid) were selected as model active drugs. Ibuprofen was granulated using a GPCG-1 fluid bed processor prior to tableting, to improve the particle size and particle flow properties. In this process a 2(3) factorial design was implemented to evaluate the optimum process parameters such as spray rate, inlet air temperature and the inlet air velocity. The statistical model selected was Y(ijkl) = mu + tau(i) + beta(j) + theta(k) + (taubeta)ij + (betatheta)jk + (tautheta)ik + (taubetatheta)ijk + epsilon(ijkl). The factorial design showed that the spray rate, inlet air temperature, and inlet air velocity had a significant effect (p value <0.05) on the particle size. Significant improvement was observed in the flow properties of the granules. The granules were coated with Kollicoat SR30D dispersion using top spray method in the fluid bed processor. The dissolution studies showed that the release of ibuprofen decreased with an increase in the coating levels of Kollicoat SR 30 D. In the case of ascorbic acid, preparation of sustained release coated commercial granules was not possible due to the difficulty in coating a highly soluble drug particle. However, the coated granules when compressed into tablets showed some sustainability. Ibuprofen tablets manufactured with coated granules with a 15 g polymer for 300 g batch showed dissolution parameters of t50 and t90 at 4.2 hr and 7.5 hr, respectively. An approximate zero-type of release was observed when the polymer content was increased to 45 g for 300 g batch. Ascorbic acid tablets made with coated commercial granules having a total polymer content of 45 g per a 500 g batch showed an average dissolution t50 and t90 at 1.0 hr and 4.55 hr, respectively. When the total polymer content was increased to 60 g, per 500 g, the average dissolution t50 and t90 delayed to 1.40 hr and 7.20 hr, respectively.

Analysis of Variance↗
PubMed2006

New AZT conjugates as potent anti-HIV agents.

In an attempt to discover anti-HIV agents with much reduced cytotoxicity from the currently available HIV-reverse transcriptase inhibitors, AZT conjugates of cholanic acids, 2-imidazolidone-4-carboxylic acid and its derivatives, and N,N'-disubstituted 5-hydroxy-tetrahydropyrimidin-2-ones have been synthesized and their anti-HIV profiles determined with CEM-SS cell line. The AZT conjugates with 2-imidazolidone-4-carboxylic acid and 2-pyrrolidone-5-carboxylic acid through an ester linkage, and with N,N'-diphenyl-5-hydroxy-tetrahydropyrimidin-2-one through a succinate tether showed significantly higher therapeutic indexes than AZT while they also retained or enhanced AZT's anti-HIV activity. Thus, structural features that favor the desired therapeutic profile of the conjugates appear to include a five-membered ring cyclic urea or lactam, and six-membered ring cyclic urea with N,N'-diphenyl substitution.

Anti-HIV Agents↗
PubMed1995

Permeability of commercial solvents through living human skin.

A procedure has been developed for measuring the steady state rate of permeation of commercial solvents through living human skin. To get the most consistent results, it was necessary with some solvents to normalize the solvent permeation rate of a given skin sample with its [3H]water permeation rate. For other solvents this was not necessary, so the un-normalized data were used. High [3H]water permeation rate also was used as a criterion for "defective" skin samples that gave erroneous permeability rates, especially for solvents having slow permeability. The linearity of the steady state data was characterized by calculation of the "percent error of the slope." The following permeability rates (g/m2h) of single solvents were measured: dimethyl sulfoxide (DMSO), 176; N-methyl-2-pyrrolidone, 171; dimethyl acetamide, 107; methyl ethyl ketone, 53; methylene chloride, 24; [3H]water, 14.8; ethanol, 11.3; butyl acetate, 1.6; gamma-butyrolactone, 1.1; toluene, 0.8; propylene carbonate, 0.7; and sulfolane, 0.2. The effect of [3H]water saturation on the shape of the presteady state portion of the permeation curve was determined and found to be very dependent on the solvent. The permeability of mixtures of DMSO and octyl acetate were measured. No octyl acetate was detected and the permeability of DMSO was proportional to its mole fraction in the mixture. The effect of two hours of solvent exposure on the viability of skin (based on DNA synthesis) was measured and found to be very dependent on the solvent.

Acetates↗
PubMed1981

[The contribution of betaine and glutamic acid to nitrogen digestion and balance during feeding of vinasse to growing pigs].

A conventional balance trial was conducted with growing pigs to study to what extent betaine and glutamic acid contained in vinasse (condensed molasses solubles) contribute to N digestion and balance. Five pigs each were given either a basal diet (95% ground barley + 5% cellulose) or a mixed ration of 77% basal diet plus 23% vinasse, based on dry matter (DM). The vinasse contained, per kg DM, 29.6 g N, 27.7 g NPN, 22.5 g betaine, 32.9 g "free" total L-glutamic acid, of which 96% was pyrrolidone carboxylic acid plus glutamine. For these N fractions of the vinasse, mean apparent digestibilities were 44.7, 63.8, 99.8 and 97.6%, respectively. Accordingly, betaine and total glutamic acid contributed 20 and 23%, respectively, of the apparently digestible total N of the vinasse. The pigs given vinasse excreted, per day, 257 mg more betaine and 364 mg more trimethylamine-N-oxide with their urine than the group given the basal diet. The contribution of betaine N of the vinasse to the N balance of the pigs on the mixed ration amounted to 11%.

Animal Feed↗
PubMed2001

Effects of adhesives and permeation enhancers on the skin permeation of captopril.

To formulate a transdermal drug delivery system of captopril, monolithic adhesive matrix type patches containing 20% captopril, different pressure-sensitive adhesives, and various permeation enhancers were prepared using a labcoater. The effects of the adhesives and permeation enhancers on skin permeation of captopril from the prepared patches were evaluated using Franz diffusion cells fitted with excised rat skins. The permeation rate of the drug through the excised skin was dependent on the type of polyacrylate copolymers studied. Fatty alcohols resulted in a pronounced enhancing effect on the skin permeation of captopril, while dimethyl sulfoxide, N-methyl-2-pyrrolidone, oleic acid, Transcutol, and polysorbate 20 showed no significant enhancing effect. The permeation-enhancing effect of the fatty alcohols reached the maximum at the level of 100%. Based on these results, a captopril patch may be developed with further optimization.

Acrylates↗
PubMed2002

Transdermal delivery of physostigmine: effects of enhancers and pressure-sensitive adhesives.

The purpose of this study was to investigate the effects of various pressure-sensitive adhesives (PSA) on the percutaneous absorption of physostigmine across hairless mouse skin. In addition, the influences of various vehicles and polyvinylpyrrolidone (PVP) on the percutaneous absorption of physostigmine from PSA matrix across hairless mouse skin were evaluated using a flow-through diffusion cell system at 37 degrees C. Physostigmine showed the highest permeability from silicone adhesive matrix, followed by polyisobutylene (PIB), styrene-isoprene-styrene (SIS), acrylic, and styrene-butadiene-styrene (SBS) matrix. Among acrylic adhesives, the permeability of physostigmine was the highest from grafted acrylic adhesive. Polyvinyl pyrrolidone inhibited the crystallization of physostigmine in the PIB adhesive matrix and enhanced the permeability of physostigmine from the PIB adhesive matrix. When esters of sorbitol and fatty acid, polyethylene glycol (PEG) alkyl esters, and caprylic/capric triglycerides were tested, the more lipophilic was a surfactant, the higher the permeation rate within the same group of surfactants. The enhancement effect of PEG derivatives was lower than that of non-PEG derivatives. Among non-linear fatty acid derivatives, linoleate derivatives showed higher permeability of physostigmine than oleate derivatives. This study showed that several non-ionic surfactants, including PEG-20 evening primrose glyceride, enhanced the permeation of physostigmine across hairless mouse skin better than oleic acid.

Adhesives↗
PubMed2003

Evaluation of critical formulation factors in the development of a rapidly dispersing captopril oral dosage form.

New methods of manufacture have enabled the creation of novel dosage forms with unique rapid-dispersion properties. This study combines one such technique with a statistical experimental design to develop dosage forms from captopril, an angiotensin-converting enzyme inhibitor used to treat cases of hypertensive emergency. The TheriForm process, a novel microfabrication technique, was used to build the dosage forms in a layer-by-layer fashion. Three key formulation factors were chosen for the design of experiments. A modified central composite design (Box-Behnken design) was used to maximize the efficiency of the experiments. A total of 13 distinct formulations were fabricated and tested, using mannitol as the bulk excipient. In addition, three replicates of the center point were tested to assess variability and experimental error. These formulations were tested for speed of dispersion (flash time), active content, hardness, friability, and moisture absorption. Regression analysis was performed to fit data responses to quadratic equations. Excellent dose accuracy (95% to 102% of target) and content uniformity (between 1.03% to 2.84%) were observed from all experimental formulation batches. As expected, the choice of powder additive (maltitol, maltodextrin, polyvinyl pyrrolidone), level of additive (2.5% to 7.5%), and saturation level of the binder liquid (45% to 65%) were all found to be significant factors for the TheriForm process. The regression analysis suggested that a rapidly dispersing dosage form of optimal physical properties would be obtained when a powder mixture of mannitol (97.5%) and maltitol (2.5%) is used at a saturation level of 45%. In conclusion, rapidly dispersing captopril oral dosage forms were successfully fabricated and tested. A wide range of physical properties, flash time, and hardness, were determined experimentally, and the effects of key formulation factors were identified.

Administration, Oral↗
PubMed2004

Process and formulation variables affecting the performance of a rupturable capsule-based drug delivery system with pulsatile drug release.

The objective of this study was to optimize several process and formulation parameters, which influence the performance of a rupturable, pulsatile drug delivery system. The system consisted of a drug-containing hard gelatin capsule, a swelling layer of croscarmellose (Ac-Di-Sol) and a binder, and an outer ethylcellulose coating. Polyvinyl pyrrolidone (Kollidon 90F) was superior to HPMC and HPC as a binder for the swelling layer with regard to binding (adherence to capsule) and disintegration properties of the swelling layer. The capsule-to-capsule uniformity in the amount of swelling layer and outer ethylcellulose coating, which significantly affected the lag time prior to rupture of the capsule, was optimized by decreasing the batch size, and by increasing the rotational pan speed and the distance between the spray nozzle and the product bed. The type of baffles used in the coating pan also affected the layering uniformity. Fully-filled hard gelatin capsules had a shorter lag time with a higher reproducibility compared to only half-filled capsules, because the swelling pressure was directed primarily to the outer ethylcellulose coating and not to the inner capsule core. Stability studies revealed that the lag time of the capsules was stable over a 240-day period when the moisture content was kept unchanged.

Capsules↗