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This study applied the concept of Quality by Design (QbD) to tablet dissolution. Its goal was to propose a quality control strategy to model dissolution testing of solid oral dose products according to International Conference on Harmonization guidelines. The methodology involved the following three steps: (1) a risk analysis to identify the material- and process-related parameters impacting the critical quality attributes of dissolution testing, (2) an experimental design to evaluate the influence of design factors (attributes and parameters selected by risk analysis) on dissolution testing, and (3) an investigation of the relationship between design factors and dissolution profiles. Results show that (a) in the case studied, the two parameters impacting dissolution kinetics are active pharmaceutical ingredient particle size distributions and tablet hardness and (b) these two parameters could be monitored with PAT tools to predict dissolution profiles. Moreover, based on the results obtained, modeling dissolution is possible. The practicality and effectiveness of the QbD approach were demonstrated through this industrial case study. Implementing such an approach systematically in industrial pharmaceutical production would reduce the need for tablet dissolution testing.

Objective: This work evaluates the functionalities of different superdisintegrants (SD) for manufacturing orodispersible mini tablets (ODMT) by direct compression., Methods: Twenty-three formulations varying in SD type, concentration, and lubricant were used to manufacture ODMT. The ODMT were then characterized for the following properties: friability, porosity, tensile strength, in vivo and in vitro disintegration time (DT)., Results: The results show that the presence, type, and concentration of SD did not influence friability, porosity, or tablet tensile strength. With regards to in vivo DT, only cross-linked poly (vinyl pyrrolidone) improved DT in all the tested formulations. Results also showed that when using microcrystalline cellulose (MCC) above 20% in the formulation, DT is longer. Cross-linked carboxymethyl cellulose accelerates DT when the MCC content is less than 20%. As for cross-linked carboxymethyl starch and calcium alginate showed no improvement on DT. Results for in vitro DT were all shorter than in vivo results and there was no correlation with the in vivo evaluation., Conclusions: This study shows that there is a need to develop better in vitro testing that precisely simulates in vivo conditions and that are adapted to ODMT. This standardization of the test methods for ODMTs must be accompanied by an improvement in the comprehension of SD mechanisms.

Context: High-amylose sodium carboxymethyl starch (HASCA) was recently proposed as a material for oral, sustained drug-release tablets prepared by direct compression. It was produced on a pilot scale, but appeared to be unsuitable for tableting and sustained drug release. Pilot-scale dry powder HASCA was dispersed in hot water and then precipitated with ethanol to give a dry powder presenting the required properties, but very high volumes of ethanol were used to recover the product., Objective: A process was therefore designed to transform totally amorphous pregelatinized HASCA by spray-drying into a suitable sustained drug-release excipient for matrix tablets while decreasing ethanol quantities., Results and Discussion: During the first manufacturing step, that is, heating of the initial hydro-alcoholic suspension, powder and water concentrations are key parameters for the acquisition of excellent binding properties. Hence, a variable ratio of amylose Vh, a crystalline polymorph of amylose, to the amorphous form, is observed depending on the key parameter values. As the most crystalline samples give the weakest tablets, binding properties do not appear to be linked to the presence of a Vh form of amylose. On the other hand, a high water concentration results in excessive tablet strength, that is, inverse conditions leading to the appearance of a Vh form of amylose. Finally, variations in hydro-alcoholic composition appear to affect only tableting properties and do not influence the drug-release rate., Conclusion: A process designed to transform totally amorphous pregelatinized HASCA by spray-drying is proposed for easier, economical industrial HASCA production.

A study to enhance the dissolution rate of ibuprofen, a poorly water-soluble drug, was carried out through combining specific formulations and processes with the addition of a hydrophilic carrier for the preparation of microparticles. Microparticle production was performed by spray drying ibuprofen microsuspensions formulated in an aqueous system with the addition of ethanol containing Aerosil 200 and Tween 80. We were able to consistently produce microparticles as much as 40% of the dry weight of the input microsuspension. Spray-dried microparticles were characterized by scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, laser diffractometer mastersizer, and infrared spectroscopy. No modification to the crystalinity and chemical structure of ibuprofen was observed. Dissolution of ibuprofen microparticles reached 100% in 3 minutes compared with less than 10% for unmodified ibuprofen. We concluded that both by the modification of formulation and the spray drying process it is possible to increase the dissolution rate of the tested model drug.

Because psychrometry takes into account a great number of variables reflecting the quality of the drying air, it is an interesting tool to improve the control and the optimization of the spray drying process. In this article the authors study the evolution of the psychrometric variables according to the values taken by four inlet parameters (inlet air temperature, liquid flow rate, solid concentration of the spray dried liquid, and nature of the product). The results highlighted the existence of mathematical models making it possible to optimize the process, but also to underline the influence of the nature of the product on the drying mechanism.

In view of its localization, brain abscess (BA) usually requires medical and surgical care. A broad spectrum of bacteria is involved. Recent reports stress the increasing frequency of anaerobes, but their impact has not been well evaluated. A retrospective review was conducted of all episodes of documented BA admitted in a tertiary-care hospital over a 10 y period. BA due to anaerobic bacteria (group A) were compared with other cases (group B) to determine the frequency and eventual characteristics of BA with isolated anaerobic bacteria. Between 1991 and 2000, BA were diagnosed in 42 patients (28M, 14F, mean age 54.6 y). No differences in clinical features and laboratory findings were found between patients with BA caused by anaerobic (n = 22) and only aerobic (n = 20) bacteria. Using appropriate microbiological techniques, 41 anaerobic bacteria strains were isolated in 22 of 42 patients (52.4%) with BA. Anaerobic bacteria were associated with aerobic strains in 5 patients (12%), whereas in 17 patients (40.5%) only anaerobic strains were isolated in cerebral puncture cultures. The most frequently isolated species were Fusobacterium nucleatum (n = 14), Prevotella sp. (n = 8), Actinomyces sp. (n = 6) and Bacteroides sp. (n = 4). Compared with group B, group A had more cases of a single abscess (p = 0.03) and ear, nose and throat (ENT) as a source of infection (p = 0.04), and seemed to have a better outcome (p = 0.07). These results emphasize the important role that anaerobic bacteria play in BA. The presence of such pathogens must be evoked when faced with a single abscess, an ENT infection, or both. Therapy should take into account this high frequency.

The present work investigates the preparation and the release of acetaminophen from spray-dried microparticles. Two cellulose derivatives were tested as sustaining agents: microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (NaCMC). In-vitro dissolution studies were carried out in dissolution media of different pH. With MCC, the adsorption of acetaminophen on the surface or in the pores of the polymer does not allow a significant sustained release of the drug, which completely dissolves in 1 h. Conversely, the use of NaCMC retards the release of acetaminophen over a period of 6-8 h. The drug release depends on the plasticizer used and on the pH of the dissolution medium, and the mechanism consists essentially in the diffusion of the drug through the swollen polymeric matrix. The pH dependence observed can be correlated with a lower hydrophylicity of the polymer in acidic medium, which retards gel formation.

Microcrystalline cellulose (MCC), sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), and ethylcellulose (EC) were used for the production of time-controlled acetaminophen delivery systems using a spray-drying technique. The influence of factors such as polymer concentration, inlet temperature, and drug/polymer ratio were investigated. The product yields were a function of the type and concentration of the polymer, with the highest values being reached from feeds containing 1% MCC and EC. Parameters of 1% polymer concentration and an inlet temperature of 140 degrees C gave rise to optimal processing conditions. Using these parameters, the influence of some adjuncts, such as polyethylene glycol 6000 (PEG 6000), dibutyl sebacate (DBS), polyvinylpyrrolidone (PVP), and carboxylic acids such as citric acid (CA), phthalic acid (PA), succinic acid (SA), tartaric acid (TA), and oxalic acid (OA), on the spray-drying process was evaluated. Of the additives tested, PVP (with MCC), DBS (with EC), and PEG 6000 (with NaCMC) induced yield decreases from 70% to 49%, 66% to 39%, and 37% to 17%, respectively. As for carboxylic acids (with NaCMC), similar or better performances of 43%, 45%, 47%, and 49% were obtained with SA, OA, PA, and TA, respectively. Dissolution studies in pH 1 dilute HCl and pH 6.8 phosphate buffer dissolution media showed that formulations consisting of 1% polymer with a drug/polymer ratio of 1/1 exhibited the slowest drug release, with the spheroids coated with NaCMC and HEC showing the longest T50% values (with 45 and 53 min at pH 1 and 49 and 55 min at pH 6.8, respectively). Slightly better sustained drug release in pH 6.8 dissolution medium was reached, showing the following trend: HEC > NaCMC > MCC > EC > HPMC. Concerning the additives, the trends in dissolution T50% of drug revealed TA > SA > CA > OA > PVP > PA > DBS in acidic pH 1 dissolution medium and PVP > OA > TA > SA > PA > CA > DBS in phosphate buffer at pH 6.8.