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.

Developability assessment in pharmaceutical industry: An integrated group approach for selecting developable candidates.

This article describes the role and responsibilities of the Developability Assessment Group (DAG), a pharmaceutical Research and Development (R&D) subgroup, which supports drug discovery and development scientists with screening, developability assessment, and selection of new molecular entities (NMEs) for clinical studies. A strong collaboration between discovery group and DAG is essential for selecting the right NMEs for late-stage development, and consequently decreasing the NME attrition rate in late-stage development as well as in bringing down the associated cost and timelines. The investigations performed by DAG for evaluating research leads as well as the significance of these investigations in the developability assessment, the value of cutting edge tools and technologies, and the usefulness of the data in the decision making process are discussed in this review. Developability assessment of NMEs often includes physicochemical and biopharmaceutical characterization, development of suitable formulations for pharmacokinetic (PK), efficacy, and toxicity studies, selection of suitable physical form (salt, polymorph, etc.), and formulation development for phase I clinical studies. Overall DAG activities not only contribute to streamlining efficacy-toxicology evaluation, but also in building developability screens, which allow pharmacologically effective, minimally toxic, and developable candidates to reach the clinic and eventually to the market.

Comprehensive validation scheme for in situ fiber optics dissolution method for pharmaceutical drug product testing.

There has been a growing interest during the past decade in the use of fiber optics dissolution testing. Use of this novel technology is mainly confined to research and development laboratories. It has not yet emerged as a tool for end product release testing despite its ability to generate in situ results and efficiency improvement. One potential reason may be the lack of clear validation guidelines that can be applied for the assessment of suitability of fiber optics. This article describes a comprehensive validation scheme and development of a reliable, robust, reproducible and cost-effective dissolution test using fiber optics technology. The test was successfully applied for characterizing the dissolution behavior of a 40-mg immediate-release tablet dosage form that is under development at Novartis Pharmaceuticals, East Hanover, New Jersey. The method was validated for the following parameters: linearity, precision, accuracy, specificity, and robustness. In particular, robustness was evaluated in terms of probe sampling depth and probe orientation. The in situ fiber optic method was found to be comparable to the existing manual sampling dissolution method. Finally, the fiber optic dissolution test was successfully performed by different operators on different days, to further enhance the validity of the method. The results demonstrate that the fiber optics technology can be successfully validated for end product dissolution/release testing.

Robust calibration design in the pharmaceutical quantitative measurements with near-infrared (NIR) spectroscopy: Avoiding the chemometric pitfalls.

Quantification analysis with near-infrared (NIR) spectroscopy typically requires utilizing chemometric techniques, such as partial least squares (PLS) method, to achieve the desired selectivity. This article points out a major limitation of these statistical-based calibration methods. The limitation is that the techniques suffer from the potential for chance correlation. In this article, the impact of chance correlation on the robustness of PLS model was illustrated via a pharmaceutical application with NIR to the content uniformity determination of tablets. The procedure involves evaluating the PLS models generated with two sets of calibration tablets incorporated with distinct degree of concentration correlation between the active pharmaceutical ingredient (API) and excipients. The selectivity and robustness of the two models were examined by using a series of data sets associated with placebo tablets and tablets incorporated with variations from excipient content, hardness and particle size. The result clearly revealed that the strong correlation observed in the PLS model created by the correlated design was not solely based on the API information, and there was an intrinsic difference in the variances described by the two calibration models. Diagnostic tools that enable the characterization of the chemical selectivity of the calibration model were also proposed for pharmaceutical quantitative analysis.

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.

Phase behavior of amorphous molecular dispersions II: Role of hydrogen bonding in solid solubility and phase separation kinetics.

PURPOSE: To determine the factors influencing "solid solubility" and phase separation kinetics of drugs from amorphous solid dispersions. METHODS: Solid dispersions of griseofulvin-poly(vinyl pyrrolidone) (PVP) and indoprofen-PVP were prepared using solvent evaporation technique. Dispersions demonstrating single Tg were exposed to 40 degrees C/69% RH for 90 days. Drug solid solubility in the polymer and phase separation rates were determined from changes in Tg of solid dispersions. FTIR spectroscopy and XRD were used to characterize drug-polymer interactions and drug crystallinity, respectively. RESULTS: Freshly prepared solid dispersion of up to 30% w/w griseofulvin and indoprofen were molecularly miscible with PVP. Hydrogen bonding was evident in indoprofen-PVP, but not in griseofulvin-PVP dispersions. When exposed to 40 degrees C/69% RH, griseofulvin phase separated completely, whereas the solid solubility of indoprofen was determined as 13% w/w. The first-order rate constants of phase separation for 10%. 20%, and 30% w/w griseofulvin dispersions were estimated as 4.66, 5.19, and 12.50 (x10(2)) [day(-1)], and those of 20% and 30% w/w indoprofen dispersions were 0.62 and 1.25 (x10(2)) [day(-1)], respectively. CONCLUSIONS: Solid solubility of griseofulvin and indoprofen in PVP is approximately 0% w/w and approximately 13% w/w, respectively. Drug-polymer hydrogen bonding in indoprofen-PVP dispersions favors solid solubility. Phase separation rate of drug from the solid dispersions depends on the initial drug content and the nature of drug-polymer interactions.

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).

Phase behavior of amorphous molecular dispersions I: Determination of the degree and mechanism of solid solubility.

PURPOSE: To understand the phase behavior and the degree and mechanism of the solid solubility in amorphous molecular dispersions by the use of thermal analysis. METHODS: Amorphous molecular dispersions of trehalose-dextran and trehalose-PVP were prepared by co-lyophilization. The mixtures were exposed to 23 degrees C, 40 degrees C, and 50 degrees C [75% relative humidity (RH)] and 23 degrees C (69% RH) storage conditions, respectively. Thermal analysis was conducted by modulated differential scanning calorimeter (MDSC). RESULTS: Upon exposure to moisture, two glass transition temperatures (TgS), one for phase-separated amorphous trehalose (Tg1) and the other for polymer-trehalose mixture (Tg2), were observed. With time, Tg2 increased and reached to a plateau (Tg(eq)), whereas Tg1 disappeared. The disappearance of Tg1 was attributed to crystallization of the phase-separated amorphous trehalose. It was observed that Tg(eq) was always less than Tg of pure polymer. The lower Tg(eq) when compared to Tg of pure polymer may be the result of solubility of a fraction of trehalose in the polymers chosen. The miscible fraction of trehalose was estimated to be 12% and 18% wt/wt in dextran at 50 degrees C/75% RH and 23 degrees C/75% RH, respectively, and 10% wt/wt in PVP at 23 degrees C/69% RH. CONCLUSIONS: Mixing behavior of trehalose-dextran and trehalose-PVP dispersions were examined both experimentally and theoretically. A method determining the "extent of molecular miscibility," referred to as "solid solubility," was developed and mechanistically and thermodynamically analyzed. Solid dispersions prepared at trehalose concentrations below the "solid solubility limit" were physically stable even under accelerated stability conditions.

Development of clinical dosage forms for a poorly water soluble drug I: Application of polyethylene glycol-polysorbate 80 solid dispersion carrier system.

Different formulation approaches were evaluated to ensure that the formulation of a poorly water soluble compound chosen during early development achieves optimum bioavailability. The insoluble compound has an aqueous solubility of 0.17 micro g/mL at 25 +/- 1 degrees C, a relatively high permeability (Caco2 P(app) = 6.1 x 10(-4) cm/min), and poor bioavailability in dogs (dry blend formulation). Based on the prediction by GastroPlus, the oral absorption of this compound is sensitive to its apparent solubility and particle size. The oral bioavailability of three different formulations was compared in a dog model: a cosolvent-surfactant solution, a solid dispersion in a mixture of polyethylene glycol 3350 and polysorbate 80, and a dry blend of micronized drug with microcrystalline cellulose. In absence of a parenteral injection, the bioavailability of the solution was considered to be 100%, and the relative oral bioavailability of the three formulations was 100, 99.1, 9.8, respectively. Comparable bioavailability was obtained with the solid dispersion and the cosolvent-surfactant solution, both of which showed a 10-fold higher bioavailability than the dry blend. Thus, a 20 mg dose strength capsule containing the solid dispersion formulation was selected for clinical development. The selected solid dispersion system was physically and chemically stable for at least 16 months at 25 degrees C/60% RH. In conclusion, the bioavailability of a poorly water soluble drug was greatly enhanced using the solid dispersion formulation containing a water soluble polymer with a surface active agent.