Determinaion of Hard Gelatin Capsule Brittlenss Using a Motorized Compression Test Stand

Abstract

Hard gelatin capsules are solid dosage forms containing powders, granulations, or pellets enclosed in a hard soluble shell. Recent guidelines for submitting documentation for the stability of human drugs and biologics to the FDA have requested test data for capsule brittleness. A simple test has been developed using a compression gauge to quantify the force required to fracture and/or shatter hard gelatin capsules. The data generated from this test can be utilized for dosage form stability assessment as well as quality control and quality assurance of capsules prior to their use in dosage from manufacture.     

Time domain 1H NMR as a new method to monitor softening of gelatin and HPMC capsule shells

Defined mechanical properties are an essential requirement for any pharmaceutical dosage form and this is particularly important in the case of liquid-filled capsules. Changes in the mechanical properties may be induced by exposure of the capsules to humidity or by a shift of the water equilibrium that typically occurs when hydrophilic or amphiphilic fill masses are used, for example, in self-emulsifying drug delivery systems. This study aims to characterize the softening of empty hard gelatin and hydroxypropyl methylcellulose (HPMC) capsules by means of mechanical tests, a Bareiss hardness test, and a stiffness test using a texture analysis method. A benchtop time domain NMR method is applied in addition to characterize the physico-chemical state of water in the capsule shells and to correlate this with the results of the mechanical tests. Hardness and stiffness measurements resulted in corresponding values, showing a softening for both capsule materials in a humid environment, which was most pronounced beyond 60% relative humidity. The capsules made of gelatin exhibited in general higher stiffness and hardness values compared to the HPMC capsules. The physico-chemical state of water in the capsule shells, as probed by a time domain NMR method, was interpreted in terms of a population balance model. Three different water populations were identified that differ in their molecular mobility, as indicated by their characteristic spin-lattice relaxation times, T1. The most loosely bound water fraction dominated in the capsule shells in the range beyond 60% relative humidity. Numerical correlation of the data led to a heuristic equation between the NMR-derived fraction of loosely bound water in the capsule shells and their mechanical stiffness and hardness. Adequate models were obtained for both capsule types, gelatin, and HPMC. Mechanical measurements of pharmaceutical capsules are generally destructive and time consuming. Testing is usually performed in an analytical laboratory, off-line from the manufacturing process, and involves only a small number of samples. Based on the here presented correlation between mechanical stiffness measurements and benchtop time domain NMR data, the latter method may be used as a nondestructive alternative for mechanical testing. This study also opens the possibility to investigate liquid-filled capsules and to establish a process analytical technology (PAT) during manufacturing.     

The In Vitro Dissolution of Theophylline from Different Types of Hard Shell Capsules

ABSTRACT

The in vitro dissolution of theophylline from two-piece hard shell capsules has been investigated using different types of capsule shells (gelatin, gelatin/polyethylene glycol, hydroxypropyl methylcellulose), different formulations, different capsule fill weights, and different tamping forces. Analysis of variance confirmed that the formulation and the capsule shell materials were the most important factors influencing drug dissolution. The maximum extent of drug dissolution was significantly increased when hydroxypropyl methylcellulose (HPMC) capsules were used. The mean dissolution time (MDT) was significantly reduced, indicating a faster dissolution rate of the drug from HPMC capsules. The addition of microfine cellulose to the formulations as filler reduced the MDT in all cases, whereas the addition of lactose monohydrate did not enhance drug dissolution. The study confirmed that a change from gelatin hard shell capsules to gelatin/PEG or HPMC hard shell capsules should not pose problems with respect to drug absorption or bioavailability.     

The in vitro dissolution of theophylline from different types of hard shell capsules

The in vitro dissolution of theophylline from two-piece hard shell capsules has been investigated using different types of capsule shells (gelatin, gelatin/polyethylene glycol, hydroxypropyl methylcellulose), different formulations, different capsule fill weights, and different tamping forces. Analysis of variance confirmed that the formulation and the capsule shell materials were the most important factors influencing drug dissolution. The maximum extent of drug dissolution was significantly increased when hydroxypropyl methylcellulose (HPMC) capsules were used. The mean dissolution time (MDT) was significantly reduced, indicating a faster dissolution rate of the drug from HPMC capsules. The addition of microfine cellulose to the formulations as filler reduced the MDT in all cases, whereas the addition of lactose monohydrate did not enhance drug dissolution. The study confirmed that a change from gelatin hard shell capsules to gelatin/PEG or HPMC hard shell capsules should not pose problems with respect to drug absorption or bioavailability.     

Time Domain 1H NMR as a New Method to Monitor Softening of Gelatin and HPMC Capsule Shells

ABSTRACT

Defined mechanical properties are an essential requirement for any pharmaceutical dosage form and this is particularly important in the case of liquid-filled capsules. Changes in the mechanical properties may be induced by exposure of the capsules to humidity or by a shift of the water equilibrium that typically occurs when hydrophilic or amphiphilic fill masses are used, for example, in self-emulsifying drug delivery systems. This study aims to characterize the softening of empty hard gelatin and hydroxypropyl methylcellulose (HPMC) capsules by means of mechanical tests, a Bareiss hardness test, and a stiffness test using a texture analysis method. A benchtop time domain NMR method is applied in addition to characterize the physico-chemical state of water in the capsule shells and to correlate this with the results of the mechanical tests. Hardness and stiffness measurements resulted in corresponding values, showing a softening for both capsule materials in a humid environment, which was most pronounced beyond 60% relative humidity. The capsules made of gelatin exhibited in general higher stiffness and hardness values compared to the HPMC capsules. The physico-chemical state of water in the capsule shells, as probed by a time domain NMR method, was interpreted in terms of a population balance model. Three different water populations were identified that differ in their molecular mobility, as indicated by their characteristic spin-lattice relaxation times, T1. The most loosely bound water fraction dominated in the capsule shells in the range beyond 60% relative humidity. Numerical correlation of the data led to a heuristic equation between the NMR-derived fraction of loosely bound water in the capsule shells and their mechanical stiffness and hardness. Adequate models were obtained for both capsule types, gelatin, and HPMC. Mechanical measurements of pharmaceutical capsules are generally destructive and time consuming. Testing is usually performed in an analytical laboratory, off-line from the manufacturing process, and involves only a small number of samples. Based on the here presented correlation between mechanical stiffness measurements and benchtop time domain NMR data, the latter method may be used as a nondestructive alternative for mechanical testing. This study also opens the possibility to investigate liquid-filled capsules and to establish a process analytical technology (PAT) during manufacturing.     

Hard Gelatin Capsules – New Developments from Capsugel

Abstract

A tamper resistant hard gelatin capsule has been developed by means of a new capsule design. A very long cap reaches over the body part making manual opening almost impossible without damage to the shell.

TP-sealing is a new method of producing tamper proof hard gelatin capsules. This sealing method is suitable for all hard gelatin capsules and allows fillings such as powders, granulates, microcapsules, liquids or pastes to be used.     

Physical stability and resistance to peroxidation of a range of liquid-fill hard gelatin capsule products on extreme long-term storage

Background: The industrial take-up of liquid-fill hard capsule technology is limited in part by lack of published long-term physical and chemical stability data which demonstrate the robustness of the system.

Objective: To assess the effects of extreme long-term storage on liquid-fill capsule product quality and integrity, with respect to both the capsules per se and a standard blister-pack type (foil–film blister).

Materials and methods: Fourteen sets of stored peroxidation-sensitive liquid-fill hard gelatin capsule product samples, originating ~20 years from the current study, were examined with respect to physical and selected chemical properties, together with microbiological evaluation.

Results and discussion: All sets retained physical integrity of capsules and blister-packs. Capsules were free of leaks, gelatin cross-linking, and microbiological growth. Eight samples met a limit (anisidine value, 20) commonly used as an index of peroxidation for lipid-based products with shelf lives of 2–3 years. Foil–film blister-packs using PVC or PVC–PVdC as the thermoforming film were well-suited packaging components for the liquid-fill capsule format.

Conclusion: The study confirms the long-term physical robustness of the liquid-fill hard capsule format, together with its manufacturing and banding processes. It also indicates that various peroxidation-sensitive products using the capsule format may be maintained satisfactorily over very prolonged storage periods.     

Semisolid matrix filled capsules: an approach to improve dissolution stability of phenytoin sodium formulation

Seven semisolid fill bases were selected for the formulation of 24 capsule formulations, each containing 100 mg of phenytoin sodium. The fill materials were selected based on the water absorption capacity of their mixtures with phenytoin sodium. The fill matrices included lipophilic bases (castor oil, soya oil, and Gelucire (G) 33/01), amphiphilic bases (G 44/14 and Suppocire BP), and water-soluble bases (PEG 4000 and PEG 6000). The drug:base ratio was 1:2. Excipients such as lecithin, docusate sodium, and poloxamer 188 were added to some formulations. The dissolution rate study indicated that formulations containing lipophilic and amphiphilic bases showed the best release profiles. These are F4 (castor oil-1% docusate sodium); F10 (castor oil-3% poloxamer 188); F14 (G33/01-10% lecithin); F17 (G33/01-1% docusate sodium), and F20 (Suppocire BP). Further, the dissolution stability of the five formulations above was assessed by an accelerated stability study at 30°C and 75% RH using standard Epanutin capsules for comparison. The study included the test and standard capsules either packed in the container of marketed Epanutin capsules (packed) or removed from their outer pack (unpacked). Release data indicated superior release rates of castor oil based formulations (F4 and F10) relative to standard capsules in both the unpacked and packed forms. For instance, the extent of drug release at 30 min after 1 month was 91% for F4 and F10 and 20% for standard capsules. Drug release from packed capsules after 6 months storage was 88% for both formulations F4 and F10 and 35% for standard capsules. In conclusion, the pharmaceutical quality of phenytoin sodium capsules can be improved by using a semisolid lipophilic matrix filled in hard gelatin capsules.     

Non-Aqueous Emulsions as Vehicles for Capsule Fillings

Abstract

New vehicles were developed based on non-aqueous emulsions. They may be classified as progress or supplimentation to the actual respectively conventional filling masses for soft gelatin capsules, but also for liquid or semi-solid hard gelatin capsule filling techniques.

IN-VITRO dissolution rate studies exhibit a clear superiority of PEG filling masses about oil-wax bases, which show extremely slow release rates.

These experiencies may therefore open an interesting way of attaining better bioavailabilities in certain cases with soft gelatin capsules as well as with hard gelatin capsules.

But in the following corresponding IN-VIVO tests, which are carried out as urine recoveries, the whole loss of superiority of the PEG compounds is impressingly shown. On the contrary the PEG bases exhibit IN-VIVO the lowest recoveries, while the non-aqueous emulsions at least those with the Riboflavin indicate a tendency towards a more favorable gastrointestinal absorption.     

Imprinting on empty hard gelatin capsule shells containing titanium dioxide by application of the UV laser printing technique

The purpose of this study was to examine the application of ultraviolet (UV) laser irradiation to printing hard gelatin capsule shells containing titanium dioxide (TiO₂) and to clarify how the color strength of the printing by the laser could be controlled by the power of the irradiated laser. Hard gelatin capsule shells containing 3.5% TiO₂ were used in this study. The capsules were irradiated with pulsed UV laser at a wavelength of 355?nm. The color strength of the printed capsule was determined by a spectrophotometer as total color difference (dE). The capsules could be printed gray by the UV laser. The formation of many black particles which were agglomerates of oxygen-defected TiO₂ was associated with the printing. In the relationship between laser peak power of a pulse and dE, there were two inflection points. The lower point was the minimal laser peak power to form the black particles and was constant regardless of the dosage forms, for example film-coated tablets, soft gelatin capsules and hard gelatin capsules. The upper point was the minimal laser peak power to form micro-bubbles in the shells and was variable with the formulation. From the lower point to the upper point, the capsules were printed gray and the dE of the printing increased linearly with the laser peak power. Hard gelatin capsule shells containing TiO₂ could be printed gray using the UV laser printing technique. The color strength of the printing could be controlled by regulating the laser energy between the two inflection points.     

Influence of capsule shell composition on the performance indicators of hypromellose capsule in comparison to hard gelatin capsules

The purpose of this study was to assess the in vitro performances of “vegetable” capsules in comparison to hard gelatin capsules in terms of shell weight variation, reaction to different humidity conditions, resistance to stress in the absence of moisture, powder leakage, disintegration and dissolution. Two types of capsules made of HPMC produced with (Capsule 2) or without (Capsule 3) a gelling agent and hard gelatin capsules (Capsule 1) were assessed. Shell weight variability was relatively low for all tested capsules shells. Although Capsule 1 had the highest moisture content under different humidity conditions, all capsule types were unable to protect the encapsulated hygroscopic polyvinylpyrrolidone (PVP) powder from surrounding humidity. The initial disintegration for all Capsule 1 occurred within 3?min, but for other types of capsules within 6?min (n?=?18). Dissolution of acetaminophen was better when the deionized water (DIW) temperature increased from 32 to 42?°C in case of Capsule 1, but the effect of temperature was not significant for the other types of capsules. Acetaminphen dissolution from Capsule 1 was the fastest (i.e. >90% in 10?min) and independent of the media pH or contents unlike Capsule 2 which was influenced by the pH and dissolution medium contents. It is feasible to use hypromellose capsules shells with or without gelling agent for new lines of pharmaceutical products, however, there is a window for capsule shells manufacturing companies to improve the dissolution of their hypromellose capsules to match the conventional gelatin capsule shells and eventually replace them.     

The Influence of Disintegrant Level and Capsule Size on Dissolution of Hard Gelatin Capsules Stored in High Humidity Conditions

Six batches of hard gelatin capsules were manufactured to explore the effect of disintegrant level and capsule fill porosity on the dissolution behavior of encapsulated dosage forms after exposure to high humidity. Size 0 capsules filled with powder blends containing 10 and 25% disintegrant dissolved faster than size 2 capsules filled with identical powder blends after storage under direct high humidity exposure. Interestingly, the trend was reversed when these identical products were exposed to high humidity but stored in, and protected by, a high density bottle-polypropylene container/closure system. It is hypothesized that capsules filled with a highly compacted powder blend, which are directly exposed to high humidity form a water layer at the gelatin-powder blend interface that inactivates the disintegrant.     

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.     

The effect of poloxamer viscosity on liquid-filling of solid dispersions in hard gelatin capsules

Preliminary studies were undertaken on poloxamers to investigate their suitability for liquid-fill formulations for hard gelatin capsules. Poloxamers with viscosity in the range (0.32-2.8 Pa s) and melting point 48-58 degrees C were used as the continuous phase, with alpha-lactose monohydrate of negligible solubility in the molten poloxamers, as a model insoluble disperse phase. Physicochemical characterization by rheology, melt solidification and moisture uptake indicated that poloxamers were suitable excipients for liquid-filling in hard gelatin capsules. 10% w/w lactose/poloxamer dispersions were thixotropic and shear thinning and exhibited good capsule-filling properties, disperse-phase uniformity and satisfactory apparent viscosity at 70 degrees C.     

The Injection-Moulded Capsule

The paper describes the development of the first injection-moulded pharmaceutical capsules. Starch and gelatin capsules have been prepared and the processing conditions and properties of the resulting starch capsules are considered in detail. Comparisons are made between the processing of thermoplastics arid starch and gelatin and the starch capsule is compared with the conventional, dip-moulded hard gelatin capsule.     

The Influence of Disintegrant Level and Capsule Size on Dissolution of Hard Gelatin Capsules Stored in High Humidity Conditions

Abstract

Six batches of hard gelatin capsules were manufactured to explore the effect of disintegrant level and capsule fill porosity on the dissolution behavior of encapsulated dosage forms after exposure to high humidity. Size 0 capsules filled with powder blends containing 10 and 25% disintegrant dissolved faster than size 2 capsules filled with identical powder blends after storage under direct high humidity exposure. Interestingly, the trend was reversed when these identical products were exposed to high humidity but stored in, and protected by, a high density bottle-polypropylene container/closure system. It is hypothesized that capsules filled with a highly compacted powder blend, which are directly exposed to high humidity form a water layer at the gelatin-powder blend interface that inactivates the disintegrant.     

The preparation of prolonged action formulations in the form of semi solid matrix into hard gelatin capsules of oxprenolol I. Thermocap method

The aim of this study was to obtain prolonged action by preparing semi-solid matrices (SSM) into hard gelatin capsules using Oxprenolol as a model drug.

SSM formulations were prepared by using different lipophilic and hydrophilic pharmaceutical excipients, polyethylene glycols as channeling agent in the semi solid mass and Gelucires. The release kinetic of drug from these formulations was determined and compared with the commercial preparation in the form of polymeric matrix of this drug.

Among the generally used excipients, we have found that Gelucires were the most appropriate excipients for preparation of SSMs and drug release from these dosage forms can be improved by the method mentioned above depending on quantity and type of channeling agent which was used.     

Effect of water-Insoluble Powder Addition on Physical Properties of Gelatin Gel

Abstract

Water-insoluble powder is often dispersed in shells of commercial soft capsules for various reasons, but little reports have been published about the effect of powder addition on the physical properties of the gelatin gel. Glass powder, titanium oxide, calcium carbonate and γ-orizanol were used as model of powder. Changes of Young modulus obtained from the tensile test showed that any powder addition to the gelatin sheet made the gelatin sheet hard not by the surface effect of powder but by the volumetric effect of it. In this test, any powders had no effect on the tensile strength of the gelatin sheet because there was little interaction between each powder and the gelatin gel in the break point. The limiting strain was decreased a little up to the specific amount of each powder and then beyond the specific amount that decreased steeply in the case of glass powder and γ-orizanol. There might be a suitable range of the amount of powder for the gelatin sheet to keep the plastic flow similar to the gelatin sheet containing no powder. In this work, it was shown that the physical properties of the gelatin shell would be regulated by powder addition to the gelatin sheet.     

Effect of water-Insoluble Powder Addition on Physical Properties of Gelatin Gel

Water-insoluble powder is often dispersed in shells of commercial soft capsules for various reasons, but little reports have been published about the effect of powder addition on the physical properties of the gelatin gel. Glass powder, titanium oxide, calcium carbonate and γ-orizanol were used as model of powder. Changes of Young modulus obtained from the tensile test showed that any powder addition to the gelatin sheet made the gelatin sheet hard not by the surface effect of powder but by the volumetric effect of it. In this test, any powders had no effect on the tensile strength of the gelatin sheet because there was little interaction between each powder and the gelatin gel in the break point. The limiting strain was decreased a little up to the specific amount of each powder and then beyond the specific amount that decreased steeply in the case of glass powder and γ-orizanol. There might be a suitable range of the amount of powder for the gelatin sheet to keep the plastic flow similar to the gelatin sheet containing no powder. In this work, it was shown that the physical properties of the gelatin shell would be regulated by powder addition to the gelatin sheet.     

Formulation and physical properties of thixotropic gels for hard gelatin capsules

Thixotropic gels for filling into hard gelatin capsules at room temperature were formulated using Miglyol 829 and colloidal silicon dioxide. Initial studies on several vehicles were undertaken prior to selection of Miglyol 829 for detailed study. The rheological properties of the gels and drug/gel formulations have been investigated in detail and the results are discussed with reference to capsule filling, stability and drug release of a model drug propantheline bromide (PPBr).