Application of melt granulation technology using twin-screw extruder in development of high-dose modified-release tablet formulation.

Development of modified-release oral tablets of drug products usually requires release-modifying polymers at the level of above 50% of the total weight. This makes the development of high-dose products, especially with doses in the range of 750-1000 mg, difficult because the tablet size becomes unacceptably high. This report presents the development of high-dose modified-release formulation of an active pharmaceutical ingredient (API), imatinib mesylate, with a drug load of approximately 90%, by melt granulation using a twin-screw extruder. For an 800 mg dose, 956 mg of drug substance (salt) was needed and the final weight of tablet was approximately 1074 mg. By carefully selecting polymers based on their physicochemical properties, the release rate could be modified between desired times of 4 to >10 h for the total drug release. Mixtures of API and polymer were melt granulated at 185 °C, which is below the melting point of API (212 °C) but above the glass transition temperatures of polymers used. The confocal Raman microscopic imaging revealed that the API remained as unmelted, crystalline particles, and polymers were finely distributed on the surface and in between API particles. The formulations were found to be robust as no change in tableting and drug release properties was observed when manufacturing parameters were altered to challenge the process. The in vivo modified-release properties of formulations were demonstrated in human pharmacokinetic studies.

Application of melt granulation technology to enhance tabletting properties of poorly compactible high-dose drugs.

Using metformin HCl as the model drug and hydroxypropylcellulose (HPC) as the polymeric excipient, a melt granulation (MG) process that employs a twin-screw extruder has been developed to enhance compactibility of poorly compactible high-dose drug substances. A high (90%) drug-load tablet formulation, containing 1025 mg of active pharmaceutical ingredients and 109 mg of excipients, was produced. Drug-polymer-powder mixtures were melt granulated at a temperature above glass transition of HPC (130°C) but below melting point of metformin HCl (224°C). MG was compared with modified wet granulation (WG) and solvent granulation (SG) processes. Under identical compression force, the hardness of tablets produced was MG>SG>WG and the friability was MG

Application of melt granulation technology to enhance stability of a moisture sensitive immediate-release drug product.

The preparation of tablets by the melt granulation process was investigated to enhance chemical stability of a highly water-soluble drug substance, dipeptidylpeptidase IV (DPP-IV) inhibitor (Compound I), that is susceptible to degradation in presence of moisture. Melt granulation with a lipophilic binder (hydrogenated castor oil; Cutina HR) improved the stability of the drug, while still maintaining immediate-release characteristics of the drug product. The drug to binder ratio was shown to impact the degradation behavior of the drug product. With higher binder levels, the sensitivity of the drug to degradation under humidity conditions decreased. It is postulated that the lipophilic binder coated drug particles at the surface protecting them from the influence of moisture. The granules had good flow properties and good compressibility and tablets prepared from them exhibited low weight variation and low friability.

Measurement of surface pH of pharmaceutical solids: a critical evaluation of indicator dye-sorption method and its comparison with slurry pH method.

Two methods for the measurement of surface pH of pharmaceutical solids, namely, the dye-sorption method and the slurry pH method, were compared. High purity drug substances, instead of excipients, were used as model solids, because acidic or basic impurities present in excipients could influence slurry pH. Solid test samples were prepared by sorption of methanol-water solutions of several indicator dyes, and their diffuse reflectance UV-visible spectra were measured. The solid surface pH values were estimated by comparing base-to-acid peak ratios of the diffuse reflectance UV-visible spectra of solid samples to the calibration plots of dye solutions in aqueous standard buffers of known pH. In the slurry pH method, pH values of concentrated slurries of the compounds in water were considered to represent solid surface pH. The agreement between the two methods was mixed and depended on the compound or the indicator used. It was concluded that in many cases calibration plots of indicator dye spectra in aqueous buffers were not applicable to the solid state, and, as a result, the reliability of the method was low. The slurry method provided a simple and reliable measurement of surface pH indicating that concentrated slurry may closely represent solid surface pH.

Stabilization of the maleate salt of a basic drug by adjustment of microenvironmental pH in solid dosage form.

Tablet formulations of the maleate salt of a basic drug (I) showed a major loss in potency and a lack of mass balance upon storage under accelerated stability testing conditions. No such stability issues were observed in capsules that were compositionally similar, and even the tablet was stable when it was encapsulated in capsule shell. It was identified that the salt converts to its free base form in the microenvironment of the tablet formulation. Studies using radiolabeled drug substance showed that the free base formed in the tablet volatilized under test conditions used and was absorbed in the wall of plastic container. No mass loss was observed with encapsulated tablets since the capsule shell either protected the drug substance from volatilization or trapped any drug substance that volatilized. The conversion of the salt to free base could be related to the pH-solubility profile of the compound where the pH(max) (pH of maximum solubility) was 3.3-3.6, above which the salt would convert to base while no such conversion would occur below this pH. The microenvironmental pH of the tablet was found to be 4.3, favoring the salt-to-base conversion. A stable tablet formulation with shelf-life >3 years was successfully developed by lowering the microenvironemental pH of tablet from 4.3 to <3.0 by adding citric acid to the formulation.

Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH.

PURPOSE: To evaluate the effect of pH on solubility and dissolution rates of a model weak base, haloperidol, and two different salt forms, hydrochloride and mesylate. METHODS: pH-solubility profiles were determined by using haloperidol base, haloperidol hydrochloride, and haloperidol mesylate as starting materials; concentrated or diluted HCl or NaOH solutions were added to aqueous suspensions of solids to adjust pH to desired values. Intrinsic dissolution rates were determined using intrinsic dissolution apparatus under various pH-stat conditions. Further, approximation of diffusion layer pH was estimated from that of 10% w/w slurries of drug substances in dissolution media, which were used to correlate with intrinsic dissolution rates of haloperidol and its salt forms under different pHs. RESULTS: pH-solubility profiles of haloperidol base and its HCl salt were similar, while when the mesylate salt was used as starting material, it exhibited a higher solubility between pH 2 and 5. The higher solubility of the mesylate salt at pH 2-5 is attributed to its higher solubility product (K(sp)) than that of the hydrochloride salt. The pH-solubility profiles indicated a pH(max) (pH of maximum solubility) of approximately 5, indicating that the free base would exist as the solid phase above this pH and a salt would be formed below this pH. Below pH 1.5, all solubilities were comparable due to a conversion of haloperidol base or the mesylate salt to the HCl salt form when HCl was used as the acidifying agent. These were confirmed by monitoring the solid phase by differential scanning calorimeter. When their dissolution rates are tested, dissolution rates of the mesylate salt were much higher than those of the free base or the HCl salt, except at very low pH (<2). Dissolution rates of free base and HCl salt also differed from each other, where that of HCl salt exhibits higher dissolution rates at higher pHs. A direct correlation of dissolution rate with solubility at diffusion layer pH at the surface of dissolving solid was established for haloperidol, its hydrochloride, and mesylate salts. CONCLUSIONS: Using pH-solubility and pH-dissolution rate interrelationships, it has been established that diffusion layer pH could be used to explain the observed rank order in dissolution rates for different salt forms. A non-hydrochloride salt, such as a mesylate salt, may provide advantages over a hydrochloride salt due to its high solubility and lack of common ion effect unless at very low pH.

Effect of combined use of nonionic surfactant on formation of oil-in-water microemulsions.

PURPOSE: This study evaluated the effects of combined use of two nonionic surfactants on the characteristics (i.e., appearance, emulsification time, and particle size) of oil-in-water microemulsions generated from flurbiprofen-loaded preconcentrates. METHODS: Three phase diagrams were constructed using Capmul PG8 (propylene glycol monocaprylate) as the oil, Tween 20 (polysorbate 20) and/or Cremophor EL (polyoxyl 35 castor oil) as surfactants. A number of preconcentrates were selected based on phase diagrams: O20T80 (20% Capmul PG8, 80% Tween 20), O20C80 (20% Capmul PG8, 80% Cremophor EL), O20T40C40 (20% Capmul PG8, 40% Tween 20, 40% Cremophor EL). Flurbiprofen loading in preconcentrates was tested at 0%, 1%, 2.5%, and 5% (w/w). The resulting mixtures of these preconcentrates upon dilution 100-fold with aqueous medium were characterized by visual and microscopic observation, HPLC and photon correlation spectroscopy. RESULTS: (a) For preconcentrates using single surfactant, either O20T80 or O20C80, the dilution generated emulsions with visible cloudiness. The particle size increased as the drug loading increased; (b) for preconcentrates using two surfactants O20T40C40, the dilution generated clear microemulsions with small particle sizes (10-11nm), and the increased drug loading seemed to have little effect on the particle size. The microemulsions from preconcentrate O20T40C40 was also found to be stable at ambient temperature over 20 days without significant change in particle size at different drug loadings. Dilution with different aqueous medium, either water, or simulated gastric fluid or simulated intestinal fluid, also did not change the particle sizes of the microemulsions. CONCLUSIONS: The combined use of surfactants in preconcentrate showed the promise in generating desired self-emulsifying microemulsions with small particle size, increased drug loading, and improved physical stability. This will have significant implications in future dosage development for poorly water-soluble drugs in using self-emulsifying microemulsions drug delivery system (SMEDDS).