Studies on the In Vitro Release of Theophylline from Polyethylene Glycol-Polyvinyl Acetate Mixtures Liquid Filled into Hard Gelatin Capsules

The release of theophylline from mixtures of polythylene glycol (PEG) with polyvinyl acetate (PVAc) liquid filled into hard gelatin capsules has been studied in vitro. Results indicate that theophylline release can be controlled over a relative wide range by varying the concentration of PVAc, and that the reproducibility of the release profile is improved considerably if the PVAc concentration exceeds 2% w/w. Other results show that drug load, molecular weight of PEG, and pH of the dissolution medium also affect release profiles. In general, the experimental data are well described by a simple equation derived from Fickian diffusion kinetics, thus supporting the suggestion that drug release from this type of formulation is controlled by diffusion in solution through water-filled pores in a network of precipitated PVAc.     

Drug Release from Thermosetting Fatty Vehicles Filled into Hard Gelatin Capsules

An initial in vitro study has been conducted to evaluate liquid filled hard gelatin capsules as potential sustained release products. Using the model compounds salicylic acid (a weak acid) and tioconazole (a weak base), release characteristics from a series of thermosetting fatty vehicles (Gelucires) have been investigated. Rapid and sustained release profiles were obtained by using different vehicles. Drug release obeyed the pH-partition theory, and a general relationship between the release rate of salicylic acid and vehicle HLB was found. However, a similar relationship could not be identified for the release of tioconazole. Drug release occurred by diffusion or erosion and diffusion processes, dependent on the vehicle employed. Diffusion release occurred relatively slowly (particularly with tioconazole) therefore for the model systems an erodible carrier would be required to achieve release rates consistent with dosing oral sustained release products.     

Liquid Filled and Sealed Hard Gelatin Capsules

A method for sealing liquid filled hard gelatin capsules has been protection against oxidation, have very effective barrier/properties against bad smelling products and have short disintegration times. These properties demonstrate that the liquid filled and sealed hard gelatin capsule offers a real alternative to the soft gelatin capsule.     

Studies of Hie Effect of Powder Moisture Content on Drug Release from Hard Gelatin Capsules

The in vitro dissolution of model formulations from hard gelatin capsules containing drug: diluent powder mixtures at different moisture levels has been studied. The capsules were filled to a constant porosity of 50%. to contain either sodium barbitone or barbitone in 50:50 mixture with lactose or maize starch, the latter at one of three moisture levels. In addition, capsules containing drug alone were examined. The wettability and polarity indeces of the individual powders and binary mixtures, as well as the permeability and liquid penetration rates of powder beds were also determined.

The presence of either excipient was found to modify the time for 50% drug dissolution (t₅₀) compared with drug alone for all formulations examined, apart from the sodium barbitone: lactose capsules. The rate of drug dissolution was also dependent on the initial powder moisture content for the drug:starch formulations. Open storage of capsules at 20^%/75%. R.lt. generally increased t₅₀figures.

The findings are discussed in terms of the nature of the surfaces of the powder particles, moisture sorption phenomena and factors such as powder bed permeability and water penetitration lates.     

Modelling of Theophylline Compound Release from Hard Gelatin Capsules Containing Gelucire Matrix Granules

Abstract

Hard shell capsules containing four theophylline compounds of different solubilities (theophylline, etofylline, diprophylline and proxyphylline) were prepared with saturated polyglycolysed glycerides (Gelucires) of melting point above 45°C and HLB value below 10. A polyvalent formulation was obtained after granulation by melting and congealing and use of glyceryl behenate (Compritol) as a lubricant of the solidified suspensions. The best yields of granulation were obtained with Gelucires 64/02, 54/02 and 50/02. The influence of three parameters was studied: melting point and HLB of the Gelucires, as well as drug solubility. Drug release was found to increase as the melting point decreased and as HLB dnd drug solubility rose. Theophylline showed abnormal behaviour because     

Preformulation Studies on Solid Dispersions Containing Triamterene or Temazepam in Polyethylene Glycols or Gelucire 44/14 for Liquid Filling of Hard Gelatin Capsules

Abstract

Solid dispersions of triamterene or temazepam in polyethylene glycols or gelucire 44/14 have been investigated. The phase equilibria of the drugs and carriers were determined by Differential Thermal Analysis and Hot Stage Microscopy. Particle Size Analysis was carried out using double image microscopy, whilst phase solubility techniques and dissolution methods were used to study solubility, dissolution and ageing.

It has been shown that triamterene forms monotectics with polyethylene glycols and gelucire 44/14 and temzepam shows partial solubility. The effect of the carriers on particle size depends on the solubility of the drug in the carrier and size reduction is observed where the drug is soluble in the carrier.     

Preformulation Studies on Solid Dispersions Containing Triamterene or Temazepam in Polyethylene Glycols or Gelucire 44/14 for Liquid Filling of Hard Gelatin Capsules

Solid dispersions of triamterene or temazepam in polyethylene glycols or gelucire 44/14 have been investigated. The phase equilibria of the drugs and carriers were determined by Differential Thermal Analysis and Hot Stage Microscopy. Particle Size Analysis was carried out using double image microscopy, whilst phase solubility techniques and dissolution methods were used to study solubility, dissolution and ageing.

It has been shown that triamterene forms monotectics with polyethylene glycols and gelucire 44/14 and temzepam shows partial solubility. The effect of the carriers on particle size depends on the solubility of the drug in the carrier and size reduction is observed where the drug is soluble in the carrier.     

Formation of Sustained Release Wax Matrices Within Hard Gelatin Capsules in a Fluidized Bed

Sustained release wax matrices were formed within hard gelatin capsules during fluidization in a hot air stream. The capsules were filled with drug (propranolol HC1 or dieophylline) - wax (Precirol ATO-5 or Gelucire 50/13) powder blends and suspended in a fluidized bed to induce fusion of the wax. Upon cooling, wax matrices with embedded drug were formed in the ends of die capsules. The use of blends of waxes with different HLB values allowed good control over the drug release pattern. The drug release from the matrices was independent of the pH of the dissolution medium. Differential scanning calorimetry was used to study the physical state of the drugs in the matrices. Propranolol HC1 was insoluble and completely dispersed in the wax matrix while theophylline was partially dissolved in the wax.     

THe Incorporation and in Vitro Release Profiles of Liquid,Deliquescent or Unstable Drugs with Fusible Excipients in Hard Gelatin Capsules

Abstract

The in vitro release profiles of four liquid or deliquescent model drugs incorporated in various Gelucire^R excipients were examined. In every case, it was possible to obtain release of the active substance as rapidly as with the equivalent commercial soft gelatine capsules tested. Gelucire^R grades with high HLB values (despite having high melting points) were found to be the most favorable. Release patterns could be related to the behaviour of the Gelucire^R bases in the gastric fluid

Drug-excipient ratio played a prominent role, which differed when hydrophilic or hydrophobic Gelucire^R types were used. Storage of the capsule formulations for more than two years did not usually change the drug release profiles significantly, but chloral hydrate capsules could not be stocked for more than a few months     

THe Incorporation and in Vitro Release Profiles of Liquid, Deliquescent or Unstable Drugs with Fusible Excipients in Hard Gelatin Capsules

The in vitro release profiles of four liquid or deliquescent model drugs incorporated in various Gelucire^R excipients were examined. In every case, it was possible to obtain release of the active substance as rapidly as with the equivalent commercial soft gelatine capsules tested. Gelucire^R grades with high HLB values (despite having high melting points) were found to be the most favorable. Release patterns could be related to the behaviour of the Gelucire^R bases in the gastric fluid

Drug-excipient ratio played a prominent role, which differed when hydrophilic or hydrophobic Gelucire^R types were used. Storage of the capsule formulations for more than two years did not usually change the drug release profiles significantly, but chloral hydrate capsules could not be stocked for more than a few months     

Weight and Weight Uniformity of Hard Gelatin Capsules Filled with Microcrystalline Cellulose and Silicified Microcrystalline Cellulose

ABSTRACT

The objective of this study was to investigate the weight and weight uniformity of hard gelatin capsules filled with microcrystalline cellulose (MCC) and silicified microcrystalline cellulose (SMCC) powdered formulations. A tamping-type encapsulation apparatus was used to fill the capsules. The four formulations that were tested included MCC alone, MCC blended with fumed silica, SMCC, and high-density SMCC (SMCC-HD). The mean capsule weight and the average variation in mean capsule weight of each formulation were determined. Both SMCC products exhibited better flow than the MCC alone, with SMCC-HD being the freest flowing of the powders investigated. Capsules filled with the SMCC products had higher fill weights than those containing the MCC powders. The SMCC-containing capsules exhibited the lowest variation in weight, although these findings were not significantly different from either of the MCC-containing capsules. Significantly higher weight variations were found in capsules filled with SMCC-HD. A relationship between Carr's compressibility index and capsule weight variation was found, with more compressible materials producing more uniformly filled capsules. No relationship could be established between powder flow and capsule weight uniformity. These findings suggest that powder flow may not be a critical parameter in ensuring capsule weight uniformity when the encapsulation equipment utilizes a tamping-type filling system.     

Drug Release from Semi-Solid Matrix Systems in Hard Capsules

Abstract

The authors have prepared hard capsules containing semisolid matrix systems with fatty excipients and acetylsalicylic acid (ASA) in order to decrease the dissolution rate of this active substance. With excipients like Gélucires and Simulsols, they obtained matrix systems easy to prepare and having a good stability, at least until 37°C. These systems release in vitro acetylsalicylic acid in about 8 hours; but administered p.o. to man they release ASA too rapidly in less then 4 hours     

Release of Ibuprofen from Polyethylene glycol solid dispersions:-Equilibrium solubility approach

This work is an attempt to enhance the release of Ibuprofen by improving its aqueous solubility. This was done by dispersing the drug in a water soluble carrier such as polyethylene glycol (PEG). The solubility was found to depend on various factors such as method of preparation, carrier weight fraction and molecular weight and the pH of the medium. It was found that dispersions prepared by the fusion method gave higher solubilities than those prepared by the solvent technique. The solubility was found to vary with carrier molecular weight and its weight fraction. Decreasing the PEG molecular weight resulted in increased solubility. A polymer to drug ratio of 1:1 was found to give the highest solubility. The solubility decreased as the polymer weight fraciton was increased beyond this value. The solubility of the solid dispersion was found to be pH dependent. A greater solubility was obtained at higher pHs than at lower ones. This was attributed to the weakly acidic nature of Ibuprofen. Calculation of the heat of solution of the various systems studied showed that the non dispersed drug had a higher heat of solution than the dispersed systems. This was thought to be the cause of the higher solubility of the dispersions as compared to the original drug.     

Release of Ibuprofen from Polyethylene glycol solid dispersions:-Equilibrium solubility approach

Abstract

This work is an attempt to enhance the release of Ibuprofen by improving its aqueous solubility. This was done by dispersing the drug in a water soluble carrier such as polyethylene glycol (PEG). The solubility was found to depend on various factors such as method of preparation, carrier weight fraction and molecular weight and the pH of the medium. It was found that dispersions prepared by the fusion method gave higher solubilities than those prepared by the solvent technique. The solubility was found to vary with carrier molecular weight and its weight fraction. Decreasing the PEG molecular weight resulted in increased solubility. A polymer to drug ratio of 1:1 was found to give the highest solubility. The solubility decreased as the polymer weight fraciton was increased beyond this value. The solubility of the solid dispersion was found to be pH dependent. A greater solubility was obtained at higher pHs than at lower ones. This was attributed to the weakly acidic nature of Ibuprofen. Calculation of the heat of solution of the various systems studied showed that the non dispersed drug had a higher heat of solution than the dispersed systems. This was thought to be the cause of the higher solubility of the dispersions as compared to the original drug.     

The Gastric Emptying of Pellets Contained in Hard Gelatin Capsules

The gastric emptying of pellets analogous to those used in sustained release preparations has been studied in vivo, using gamma scintigraphy. The results show that under certain conditions, the pellets may not necessarily empty from the stomach in a randomized manner.     

The Gastric Emptying of Pellets Contained in Hard Gelatin Capsules

The gastric emptying of pellets analogous to those used in sustained release preparations has been studied in vivo, using gamma scintigraphy. The results show that under certain conditions, the pellets may not necessarily empty from the stomach in a randomized manner.     

Rheology and Filling Characteristics of Particulate Dispersions in Polymer Melt Formulations for Liquid Fill Hard Gelatin Capsules

Abstract

The rheology and capsule filling properties of molten excipients, Dynafill, Dynasan-114, Lutrol-F68, and polyethylene glycols (PEG) 6000, 8000, 10,000, and 20,000 have been investigated. Lactose (α-monohydrate) was selected as a model particulate solid with low solubility in PEG in order to investigate the effects of disperse phase particle size, concentration, and PEG molecular weight on rheology and capsule filling properties of these systems. All excipients behaved as Newtonian fluids between 65 and 90°C, which was chosen as a possible temperature range for liquid filling of hard gelatin capsules. The excipients, apart from Dynasan-114 and PEG 20,000, showed satisfactory capsule filling properties at 70°C using a semiautomatic filling machine. Dynasan-114 (viscosity = 0.012 Pass at 70°C) leaked from the seals between the hopper and pump of the filling machine, whereas PEG 20,000 (viscosity = 24 Pas at 70?C) showed bridging of the molten polymer between successive capsule bodies during the filling process. The effect of disperse phase (lactose) particle size and concentration, and continuous phase (PEG) molecular weight on the apparent viscosity and filling properties of the non-Newtonian dispersions were investigated at 70°C. Satisfactory filling of the dispersions was achieved at 70°C up to a limiting concentration of disperse phase which was dependent upon disperse phase particle size and continuous phase molecular weight, and corresponded to a pronounced increase in apparent viscosity of the dispersion.     

Effect of Particle Size,Content in Lubricant,Mixing Time and Storage Relative Humidity on Drug Release from Hard Gelatin Ampicillin Capsules

Abstract

The influence of several variables on the release of ampicillin from hard gelatin capsules is studied. 18 lots of ampicillin capsules were prepared, with the following affecting variables: a) time of mixing the materials before filling the capsules, b) ampicillin particle size, c) Content in lubricant (magnesium stearate), d) Storage under several humidity conditions. It was found that dissolution rate is significantly affected by the size of ampicillin particles. Similar effects by variation of the other parameters are observed.     

Effect of Glycine/Citric Acid on the Dissolution Stability of Hard Gelatin Capsules

Abstract

Gelatin capsule crosslinking is a well-known phenomenon that results in reduced dissolution of capsule products with the passage of time and/or under accelerated stability conditions. These studies describe one means of preventing capsule crosslinking by incorporating glycine and citric acid into a triamterene/hydrochlorothiazide 37.5/25 mg capsule formulation (triam/HCTZ). Triam/HCTZ without glycine and citric acid showed extensive capsule crosslinking and then failed the USP dissolution specification after a 4-week accelerated (40°C/85% relative humidity [RH]) stability study. Triam/HCTZ containing glycine alone showed some improvement in the dissolution stability but did not prevent gelatin crosslinking. This formulation also failed dissolution specifications after a 4-week accelerated stability study. The same results were obtained when only citric acid was incorporated into the triam/HCTZ. However when glycine and citric acid were incorporated together into the triam/HCTZ, crosslinking was completely prevented. Dissolution profiles remained the same throughout 12-week accelerated stability studies, with little or no drop in the dissolution values throughout the test period. The above results were confirmed with follow-up studies using gemfibrozil and piroxicam as model drugs. Disintegration times for gemfibrozil and piroxicam capsule formulations without glycine and citric acid increased dramatically with observed pellicle formation, but there was little or no change in the disintegration time of the model drugs formulated with glycine and citric acid. The results of these studies demonstrated that when glycine and citric acid are present in some gelatin capsule formulations, pellicle formation or crosslinking of the capsule gelatin is prevented.