Characterization of Poly(Ethylene Oxide) as a Drug Carrier in Hot-Melt Extrusion

ABSTRACT

Poly(ethylene oxide) (PEO) as a drug carrier in hot-melt extrusion was studied by using a model drug, nifedipine, in a twin-screw extruder. Binary mixtures of PEO and nifedipine have been shown to be amenable to hot-melting at a temperature as low as 70°C, well below nifedipine's melting point (172°C). Hot-stage microscopy provided visual evidence that nifedipine can form a miscible dispersion with PEO at 120°C. Complete loss of nifedipine crystallinity when extrudated at and above 120°C with a drug loading of 20% (w/w) was further confirmed by differential scanning calorimetry (DSC) and X-ray diffraction. Cross-sectional imaging of the extrudates using scanning electron microscopy indicated homogeneous drug distribution inside PEO when the processing temperature was above 120°C. Raman spectroscopy confirmed drug-PEO interactions at a molecular level. Cryo-milled extrudates showed significant improvement in dissolution rate compared to either pure nifedipine or the physical mixture of PEO and nifedipine. A state of supersaturation was achieved after 10-minute release in pH 6.8 phosphate buffer. Finally, stability study demonstrated that the solid dispersion system is chemically stable for at least 3 months under the conditions of both 25°C/60% RH and 40°C/75% RH. Overall, PEO appears to be a promising aid/carrier to solublize poorly soluble drugs through the formation of solid dispersion via hot-melt extrusion, thereby improving dissolution and absorption.     

Effect of unconventional curing conditions and storage on pellets coated with Aquacoat ECD

Purpose: Purpose of this study was to develop storage stable pellets coated with the aqueous ethylcellulose dispersion Aquacoat ECD. Methods: The influence of accelerated curing/storage conditions on the release behavior of Aquacoat/HPMC-coated drug pellets were investigated as a function of various formulations (sealing, plasticizer content, and pore-former type/amount) and process parameters (process humidity, thermal curing, and organic processing). Results: Conventionally cured Aquacoat/hydroxypropyl methylcellulose-coated pellets were storage stable at ambient conditions and 25°C/60% relative humidity (RH) but showed a decreasing drug release at 40°C/75% RH, which is a required test condition according to ICH guidelines. Conclusion: Only organic processing of dried Aquacoat or unconventionally harsh curing conditions (60°C/75% RH or 80°C) improved the storage stability of Aquacoat-coated pellets at accelerated conditions.     

Relation Between Polymorphic Transformation Pathway During Grinding and the Physicochemical Properties of Bulk Powders for Pharmaceutical Preparations

Abstract

The polymorphic transformation pathway during grinding of cephalexin (CEX), chloramphenicol palmitate (CPP) and indomethacin (IMC) were investigated. CEX was converted into noncrystalline solid at room temperature. The meta-stable forms B and C CPP was transformed into stable form A at room temperature. IMC was transformed into noncrystalline solid during grinding at 4°C, but it transformed into meta-stable form a during grinding at 30°C. The melting point (mp) of CPP and IMC were about 90°C and 160°C, respectively. CEX does not have the mp, but have the decomposition point at 190°C. The mp of CEX is higher than the decomposition point. The order of the mp for these drugs is CPP < IMC < CEX. The proportional relation between the mp and the glass transition point of the drugs had reported, therefore, in general the higher mp material has the higher glass transition point. The order of the stability for a noncrystalline solids of these drugs is CPP < IMC < CEX. The noncrystalline solid of CEX is very stable at 35°C under lower than 66% of relative humidity. The noncrystalline solid of CPP was very unstable at about 20°C, therefore, it transformed into a crystalline form very rapidly. The noncrystalline solid of IMC was stable at 4°C, but it was unstable at 30°C, therefore, after grinding it transformed into a form. These results suggest that there is a very important relation between the transformation pathway of the crystalline form during grinding and the physicochemical properties. The transformation pathway is controlled by the stability of noncrystalline solid and the presence of meta-stable crystalline form.     

Early pharmaceutical evaluation of a crystalline and hygroscopic GABAB receptor agonist

Lesogaberan is a potent gamma amino butyric acid agonist and has been evaluated for its utility in treatment of gastroesophageal reflux disease. Lesogaberan is a crystalline substance that absorbs considerable amounts of water above 65% relative humidity (RH) where it also liquifies. As a result of the hygroscopicity of the zwitterionic form an investigation of different salt forms was performed. Since the test compound is polar and lacks ultraviolet (UV) chromophore, conventional separation and detection techniques could not be used to characterise the test compound and the impurities. The analytical techniques are described, focusing on the capillary electrophoresis method with indirect UV detection for purity, the liquid chromatographic method for enantiomeric separation with derivatisation with UV chromophore and two complementary nuclear magnetic resonance (NMR) approaches (¹⁹F-NMR and ¹H-NMR) for impurities. The stability study in solution showed that solutions between pH 5 and 7 were the most stable ones, but after some time degradation occurred at room temperature. When bulk lesogaberan was stored at 25°C/60% RH no chemical degradation was observed after 1 year. At 40°C/75% RH, where the compound liquefies, a significant degradation was observed after 1 month. However, in a closed container (= 40°C) or as a napsylate salt, no degradation of lesogaberan was observed at 40°C/75% RH.     

Application of salt engineering to reduce/mask bitter taste of clindamycin

Abstract

Palatability of a formulation is one of the primary requirements for therapeutic compliance in children. Clindamycin (CLN) often prescribed to children to treat various infections. However, it has a bitter taste and bad smell. The focus of the present investigation was to develop salt of CLN with a commonly used sweetener such as cyclamic acid (CYA) to improve the palatability. The salt forms were prepared by solubilization crystallization method and characterized by Fourier transformed infrared (FTIR), Near infrared (NIR), Raman, X-ray powder diffraction, scanning electron microscopy, solubility, dissolution, and solid-state physical and chemical stability at 25?°C/60% RH and 40?°C/75% RH for 1 month and 60?°C for 2 weeks. Spectroscopic and diffraction data indicated the formation of a new solid phase, which was different from hydrochloride salt of CLN. Shape of crystal was rectangular prism. Stoichiometric ratio between CLN and CYA in the new salt CLN-CYA was 1:1 and its melting point was 85.6?°C. There was a 2.4-fold reduction in solubility of CLN-CYA at pH 4 compared with CLN-HCl. Moreover, the dissolution rate and extent were similar between the two salts and meeting USP requirement of 85% dissolution in 30?min. Salt was physically and chemically stable at 60?°C, 25?°C/60% RH, and 40?°C/75% RH conditions but hygroscopic at high humidity condition. In conclusion, new salt will provide a new avenue for the development of a palatable formulation of CLN.     

Physicochemical stability,pharmacokinetic, and biodistribution evaluation of paclitaxel solid dispersion prepared using supercritical antisolvent process

Aim: To investigate the physicochemical stability, pharmacokinetics (PK), and biodistribution of paclitaxel (PTX) from paclitaxel solid dispersion (PSD) prepared by supercritical antisolvent (SAS) process.

Methods: Physicochemical stability was performed in accelerated (40°C 70?±?5% RH) and stress (60°C) storage conditions for a period of 6 months and 4 weeks, respectively. PK and biodistribution studies were performed in rats following i.v. administration of PTX equivalent to 6 and 12?mg/kg formulations.

Results: Physical stability of PSD showed excellent stability with no recrystallization of the amorphous form. Chemical stability of PSD in terms of % PTX remaining was 98.2?±?0.6% at 6 months and 97.9?±?0.3% at 4 weeks of accelerated and stress conditions, respectively. The PK study showed a nonlinear increase in AUC with increasing dose, that is, 100% increase in dose (from 6 to 12?mg/kg) resulted in 405.90% increase in AUC. Unlike PK study, the organ distribution study of PTX from PSD showed linear relationship with dose escalation. The order of organ distribution of PTX from highest to lowest for both PSD and Taxol^® was liver>kidney>lung>brain.

Conclusions: This study demonstrated excellent physicochemical stability with insight information on the PK and biodistribution of PTX from PSD prepared by SAS process.     

Enhancing the Bioavailability of Cyclosporine A Using Solid Dispersion Containing Polyoxyethylene (40) Stearate

ABSTRACT

Solid dispersion containing polyoxyethylene (40) stearate and cyclosporine A was prepared by solvent-melt method and characterized using differential scanning calorimetry, powder X-ray diffraction, and Infrared Fourier Transform Spectroscopy (FTIR). Dissolution of the drug from solid dispersion was dramatically enhanced compared to that from the drug powder alone and physical mixture. In vivo oral bioavailability of cyclosporine A from the solid dispersion in Wistar rats was comparable to that from a commercial product, Sandimmun Neoral® (P > 0.05). The formulation is stable up to six months under 30°C/RH60% and one year at 25°C/RH 60% when packed in aluminum-polyethylene laminated bags.     

Nimodipine (NM) tablets with high dissolution containing NM solid dispersions prepared by hot-melt extrusion

Using a mixture of Eudragit^® EPO and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) (Kollidon VA64) as carriers, a nimodipine solid dispersion (NM-SD) was prepared by hot-melt extrusion (HME) to achieve high dissolution. The dissolution profiles in 900?mL 0.1?mol/L HCl showed that the drug release of NM-SD reached 90% in 1?h. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) were used to characterize the state of NM. The results obtained showed that NM was in an amorphous form in the solid dispersion (SD). NM-SD tablets (NM-T-SD) were compressed by wet granulation and direct compression, respectively. The stability of NM-T-SD was examined during a 2-month storage period (40°C, RH 75%). The results showed that the dissolution of NM-T-SD was slightly reduced after 2 months storage (40°C, RH 75%), which implied that aging occurred to some degree. However, no NM crystals could be observed by PXRD after 2 months storage for NM-T-SD (F₁₁) prepared by direct compression.     

Formulation and Stability Evaluation of Ketoprofen Sustained-Release Tablets Prepared by Fluid Bed Granulation with Carbopol® 971P Solution

ABSTRACT

The objectives of the present study were: (1) to investigate the possibility of using a Carbopol polymeric solution as granulating agent by the fluid bed granulating process; (2) to select a suitable method of tabletting for sustaining the release of ketoprofen for 12 hr; (3) to perform stability studies according to International Committee on Harmonization (ICH) guidelines and photostability on ketoprofen SR tablets; (4) to study the influence of the storage conditions on release kinetics and melting endotherm of ketoprofen; and (5) to predict the shelf-life of the ketoprofen SR tablets. Tabletting ingredients were ketoprofen, anhydrous dicalcium phosphate, Carbopol® 971P, talc, and magnesium stearate. Carbopol® 971P solution (0.8% w/v) was used as a granulating solution in the fluid bed granulator. For comparative evaluation, tablets were also prepared by direct compression and wet granulation, and subjected to dissolution. Tablets prepared by fluid bed granulation technique were stored in incubators maintained at 37, 40, 50, and 60°C, 40°C/75% RH, 30°C/60% RH, and 25°C/60% RH, and in a light chamber with light intensity of 600 ft candle at 25°C. Melting endotherms were obtained for the drug as well as the tablets during stability studies by differential scanning calorimetry. Tablets prepared by fluid bed granulation technique prolonged the release of ketoprofen better than tablets obtained by direct compression and wet granulation. Further, it complied with the requirements of ICH guidelines for stability testing. Higher temperature and humidity (40 ± 2°C/75% RH, 40°C, 50°C, and 60°C) adversely affected the rate and extent of the dissolution. Ketoprofen SR tablets stored in amber-colored bottles demonstrated a good photostability for 6 months at 600 ft candle. The shelf-life of the formulation was predicted as 32 months.     

Comparative Aging Studies of Tablets Made with Diabasic Calcium Phosphate Dihydrate and Spray Dried Lactose

Abstract

There are relatively few published reports on the aging of tablets (1-4) and thus, as an extension of previously published work, the aging of compressed tablets (prepared using either dibasic calcium phosphate dihydrate or spray^A dried lactose as matrix) has been investigated over a sixty-five day period. All tablets contained 6% amaranth as a dye tracer, 0.5% magnesium stearate as lubricant and 2.5% sodium alginate as disintegrant. Tablets were prepared by direct compression on a single punch press and stored under three sets of stress conditions: (a) 25°C, 45% relative humidity (RH); (b) 35°C, 60% RH; (c) 45°C, 75% RH.

Tablets were evaluated by appearance (visual and photography); weigh; size; hardness (Erweka); disintegration time (U.S.P.); and dissolution (U.S.P.). A transient mottling phenomenon was evident in both systems under accelerated conditions. Significant weight variations were observed at all temperatures for the dibasic calcium phosphate dihydrate system, while lactose tablets showed only slight changes in weight. Under accelerated storage conditions, hardness appears to be related to disintegration times and dissolution rates with either system. However, it is not a reliable tool at room temperature. In addition, results at accelerated conditions do not appear to be directly related to those obtained at room temperature.     

A Survey of the Stability of Omeprazole Products from 13 Countries

Abstract

The results of an independent survey of the stability of omeprazole solid dosage forms (20 mg) show that products available in many countries worldwide exhibit a very wide range of stability characteristics. Stability testing under the ICH accelerated test conditions (40°C/75% RH; 6 months) was performed on a total of 34 products obtained in 13 countries by independent sampling officers. The samples were visually examined for physical change and analyzed for their total content of impurities, remaining omeprazole, and the amount of omeprazole released in vitro. Twenty-seven of the products (79%) exhibited a change in one or more of the stability-indicating parameters during the 6-month study. These included 16 products that had more than 10% of decomposition products at 6 months and 10 other products that contained 2-10% of decomposition products at 6 months. In most samples, the formation of decomposition products was accompanied by a corresponding measurable decrease in the content of omeprazole. Of the eight samples containing less than 2% of decomposition products after 6 months storage, one showed a large reduction in the amount of omeprazole released in vitro. Another product which contained 1.2% decomposition products at 6 months released lower amounts of omeprazole in vitro at all time points than most other products. Only six products (18%) were considered to demonstrate good physical and chemical stability over the course of the study, viz. Losec Capsules (Astra, Sweden), Losec Capsules (Astra, Korea), Losec Capsules (Astra, Turkey), Miracid Capsules (Berlin Pharm. Ind. Co., Thailand), Mopral Capsules (Astra-Ifesa, Spain), and OMP Tablets (Chon Kun Dang Corp., Korea).     

Miconazole and Miconazolenitrate Chewing Gun as Drug Delivery Systems - A Practical Application of Solid Dispersion Technique

Miconazole and miconazolenitrate are antifungal drugs with poor solubilities in water and saliva. The low solubilities meant that only small amounts of the drugs - incorporated by a conventional method in chewing gum-were released during mastication. The experiments were performed on a mastication device.

In this study it was shown that application of a 20% miconazole - 80% polyethyleneglycol 6000 solid dispersion drastically improved the in vitro release of miconazole from cheving gum, when a medium similar to saliva was used. In addition to polyethyleneglycol 6000, polyvinylpyrrolidone 40000, xylitol and urea were tested as carriers. It was also shown that the release rate of miconazole from chewing gum was much greater than the release rate of miconazolenitrate.

No certain correlation could be shown between the dissolution rates of the solid dispersions measured by a stirring paddle method and the release rates of miconazole from solid dispersions in chewing gum.

The solid dispersion systems were characterized by differential scanning calorimetry. The systems containing polyethyleneglycol 6000 and xylitol were eutectic. Polyvinylpyrrolidone 40000 prevented crystallisation of miconazole when the percentage of drug in the solid dispersion was less than 50%.     

Delayed release film coating applications on oral solid dosage forms of proton pump inhibitors: case studies

Background: Formulation of proton pump inhibitors (PPIs) into oral solid dosage forms is challenging because the drug molecules are acid-labile. The aim of this study is to evaluate different formulation strategies (monolithic and multiparticulates) for three PPI drugs, that is, rabeprazole sodium, lansoprazole, and esomeprazole magnesium, using delayed release film coating applications. Method: The core tablets of rabeprazole sodium were prepared using organic wet granulation method. Multiparticulates of lansoprazole and esomeprazole magnesium were prepared through drug layering of sugar spheres, using powder layering and suspension layering methods, respectively. Tablets and drug-layered multiparticulates were seal-coated, followed by delayed release film coating application, using Acryl-EZE®, aqueous acrylic enteric system. Multiparticulates were then filled into capsules. The final dosage forms were evaluated for physical properties, as well as in vitro dissolution testing in both compendial acid phase, 0.1N HCl (pH 1.2), and intermediate pH, acetate buffer (pH 4.5), followed by phosphate buffer, pH 6.8. The stability of the delayed release dosage forms was evaluated upon storage in accelerated conditions [40°C/75% relative humidity] for 3 months. Results: All dosage forms demonstrated excellent enteric protection in the acid phase, followed by rapid release in their respective buffer media. Moreover, the delayed release dosage forms remained stable under accelerated stability conditions for 3 months. Conclusions: Results showed that Acryl-EZE enteric coating systems provide excellent performance in both media (0.1N HCl and acetate buffer pH 4.5) for monolithic and multiparticulate dosage forms.     

Optimization of the lyophilization process for long-term stability of solid–lipid nanoparticles

Objectives: To optimize a lyophilization protocol for solid–lipid nanoparticles (SLNs) loaded with dexamethasone palmitate (Dex-P) and to compare the long-term stability of lyophilized SLNs and aqueous SLN suspensions at two storage conditions.

Materials and Methods: The effect of various parameters of the lyophilization process on SLN redispersibility was evaluated. A three month stability study was conducted to compare changes in the particle size and drug loading of lyophilized SLNs with SLNs stored as aqueous suspensions at either 4°C or 25°C/60% relative humidity (RH).

Results and Discussion: Of nine possible lyoprotectants tested, sucrose was shown to be the most efficient at achieving SLN redispersibility. Higher freezing temperatures, slower freezing rates, and longer secondary drying times were also shown to be beneficial. Loading of the SLNs with Dex-P led to slightly larger particle size and polydispersity index increases, but both parameters remained within an acceptable range. Drug loading and particle shape were maintained following lyophilization, and no large aggregates were detected. During the stability study, significant growth and drug loss were observed for aqueous SLN suspensions stored at 25°C/60% RH. In comparison, lyophilized SLNs stored at 4°C exhibited a consistent particle size and showed <20% drug loss. Other storage conditions led to intermediate results.

Conclusions: A lyophilization protocol was developed that allowed SLNs to be reconstituted with minimal changes in their physicochemical properties. During a three month period, lyophilized SLNs stored at 4°C exhibited the greatest stability, showing no change in the particle size and a minimal reduction in drug retention.     

Storage Conditions for Stability Testing in the Ec,Japan and Usa; the Most Important Market for Drug Products

Abstract

Strong efforts have been undertaken to harmonise the requirements for the investigation of the stability of drug substances and drug products. Since the results of these investigations are used to assign labelling which properly reflects the stability of the substances/products under the climatic conditions encountered in the region of distribution and use, a thorough examination of the climatic conditions in the EC, Japan and the USA was conducted. According to this study, the EC, Japan and the USA may be practically assigned to a region for which there is an annual mean kinetic temperature of up to 25 degrees C.

In fact, the climatic study indicates that 25 degrees C/60 per cent RH is general well above the mean kinetic temperature for the 35 major European, Japanese and American cities in the study. In addition the mean kinetic temperature encompasses the data in warehouses as well as measured seasonal and daily fluctuations up to and above the extreme temperature of 30 degrees C allowed by the USP definition of controlled room temperature. Based upon the above, it can therefore be concluded that long term controlled room temperature labelling for the USA, Japan and the EC can be accurately assigned by applying storage condition of 25 degrees C/60 per cent RH.

Since the applied procedure to calculate and derive climatic conditions is based on the Arrhenius equation in the modified version of Hayne's relates mainly to chemical stability. In order to follow also organoleptic and physico-chemical changes storage at higher conditions is necessary for up to 6 months (40°C/75%) if a shelf live of at least three years is anticipated.

The described procedure and derived storage conditions allow considerably savings in capacity and cutting costs.     

Miconazole and Miconazolenitrate Chewing Gum as Drug Delivery Systems - A Practical Application of Solid Dispersion Technique

Miconazole and miconazolenitrate are antifungal drugs with poor solubilities in water and saliva. The low solubilities meant that only small amounts of the drugs-incorporated by a conventional method in chewing gum-were released during mastication. The experiments were performed on a mastication device.

In this study it was shown that application of a 20% miconazole - 80% polyethyleneglycol 6000 solid dispersion drastically improved the in vitro release of miconazole from cheving gum, when a medium similar to saliva was used. In addition to polyethyleneglycol 6000, polyvinylpyrrolidone 40000, xylitol and urea were tested as carriers. It was also shown that the release rate of miconazole from chewing gum was much greater than the release rate of miconazolenitrate.

No certain correlation could be shown between the dissolution rates of the solid dispersions measured by a stirring paddle method and the release rates of miconazole from solid dispersions in chewing gum.

The solid dispersion systems were characterized by differential scanning calorimetry. The systems containing polyethyleneglycol 6000 and xylitol were eutectic. Polyvinylpyrrolidone 40000 prevented crystallisation of miconazole when the percentage of drug in the solid dispersion was less than 50%.     

Miconazole and Miconazolenitrate Chewing Gun as Drug Delivery Systems – A Practical Application of Solid Dispersion Technique

Abstract

Miconazole and miconazolenitrate are antifungal drugs with poor solubilities in water and saliva. The low solubilities meant that only small amounts of the drugs – incorporated by a conventional method in chewing gum-were released during mastication. The experiments were performed on a mastication device.

In this study it was shown that application of a 20% miconazole – 80% polyethyleneglycol 6000 solid dispersion drastically improved the in vitro release of miconazole from cheving gum, when a medium similar to saliva was used. In addition to polyethyleneglycol 6000, polyvinylpyrrolidone 40000, xylitol and urea were tested as carriers. It was also shown that the release rate of miconazole from chewing gum was much greater than the release rate of miconazolenitrate.

No certain correlation could be shown between the dissolution rates of the solid dispersions measured by a stirring paddle method and the release rates of miconazole from solid dispersions in chewing gum.

The solid dispersion systems were characterized by differential scanning calorimetry. The systems containing polyethyleneglycol 6000 and xylitol were eutectic. Polyvinylpyrrolidone 40000 prevented crystallisation of miconazole when the percentage of drug in the solid dispersion was less than 50%.     

Role of new Antioxidants in the Stabilization of Ophthalmic and ear Dosage form Preparation of Hamycin

Abstract

The study involves the development of eye-ointment and ear-drop dosage form of hamycin, a polyene antifungal antibiotic, using anti-oxidants and stabilisers to enhance the stability of these dosage forms. It has been found that incorporation of hydroquinone (HQ), butylated hydroxy anisole (BHA), nordihydroguiaretic acid (NDGA), sodium deoxycholate (DSC) and ascorbyl palmitate (AP) in varying combinations in the dosage preparation have enhanced the stability and preserved physicochemical properties of the ointment for a period of 12 months period under refrigerated temperature (8+2°C) conditions. It was further observed that this dosage preparation is more stable in polyethylene glycol bases than in lanolin bases. Ear-drops dosage preparation has shown stability for 12 months period in the presence of BHA and in combination of other antioxidants under refrigerated temperature. However, ear-drops dosage form was found to be stable only for a period of 6months in ambient condition. It is therefore, recommended that these dosage preparations be stored in refrigerated conditions.     

Formulation for a novel inhaled peptide therapeutic for idiopathic pulmonary fibrosis

A caveolin-1 scaffolding domain, CSP7, is a newly developed peptide for the treatment of idiopathic pulmonary fibrosis. To develop a CSP7 formulation for further use we have obtained, characterized and compared a number of lyophilized formulations of CSP7 trifluoroacetate with DPBS and in combination with excipients (mannitol and lactose at molar ratios 1:5, 70 and 140). CSP7 trifluoroacetate was stable (>95%) in solution at 5 and 25?°C for up to 48?h and tolerated at least 5 freeze/thaw cycles. Lyophilized cakes of CSP7 trifluoroacetate with excipients were stable (>96%) for up to 4?weeks at room temperature (RT), and retained more than 98% of the CSP7 trifluoroacetate in the solution at 8?h after reconstitution at RT. The lyophilized CSP7 formulations were stable for up to 10?months at 5?°C protected from moisture. Exposure of the lyophilized cakes of CSP7 to 75% relative humidity (RH) resulted in an increase in the absorbed moisture, promoted crystallization of the excipients and induced reversible formation of CSP7 aggregates. Increased molar ratio of mannitol slightly affected formation of the aggregates. In contrast, lactose significantly decreased (up to 20 times) aggregate formation with apparent saturation at the molar ratio of 1:70. The possible mechanisms of stabilization of CSP7 trifluoroacetate in solid state by lactose include physical state of the bulking agent and the interactions between lactose and CSP7 trifluoroacetate (e.g. formation of a Schiff base with the N-terminal amino group of CSP7). Finally, CSP7 trifluoroacetate exhibited excellent stability during nebulization of formulations containing mannitol or lactose.     

Changes in Drug Release Rate: Effect of Stress Storage Conditions on Film Coated Mini-Tablets

Abstract

Film coated theophylline mini-tablets were exposed to stress storage conditions to investigate the effect of changes in temperature and relative humidity (RH) on drug release and the integrity of film coatings. The mini-tablets (3mm in diameter, weighing 20±1 mg) were film coated with polymers such as ethylcellulose with PEG (2:1), ethylcellulose with Eudragit L (2:1) and Eudragit RL. Samples were exposed isothermally at 28,35 and 45°C (constant RH ranging between 55 and 60%) for 21,90 and 180 days, as well as cyclically alternating them every 24h at 45°C, 55% RH; 28°C, 20% RH; and 5°C, 10% RH for 90 days. Dissolution profiles determined after storage were compared with those 24h after initial coating. All samples showed that the coating integrity was maintained. However, dissolution was significantly impeded to a degree directly proportional to temperature, whilst the effect of RH appeared insignificant.