Design Of Pharmaceutical Dosage Forms Research Articles

Potential pharmacokinetic interaction between orally administered drug and osmotically active excipients in pediatric polypharmacy

Poorly absorbable sugar alcohols (e.g., mannitol, sorbitol, and maltitol) are the excipients frequently contained in pediatric dosage forms. Due to their osmotically active properties, certain amount of sugar alcohols reportedly reduces oral bioavailability of concomitant drugs. This fact implies the possible pharmacokinetic interaction between orally administered drug and sugar alcohols which are present in other concomitant medications. The purpose of this study was to identify the possibility and likeliness of the osmotically active excipient-induced pharmacokinetic interaction in pediatric polypharmacy. Previously developed in silico model that captured the osmotic effect of sugar alcohols in adults was expanded to pediatric population. This mathematical model successfully explained the impaired bioavailability of lamivudine by the co-administered sorbitol in other dosage forms. In the meantime, sugar alcohol contents in marketed pediatric dosage forms were investigated by reverse engineering technology. Considering the critical administration dose of sugar alcohols estimated by in silico model, it was revealed that 25 out of 153 pediatric dosage forms were identified as possible perpetrators even under the approved administration and dosage in Japan. This study shed light on the potential pharmacokinetic interaction that cannot be dismissed throughout the pediatric pharmaceutical dosage form design and development.

Recent Advancements in Pharmaceutical Cocrystals, Preparation Methods, and their Applications.

The issue of poor aqueous solubility is a major hurdle in pharmaceutical dosage form design. A large number of active molecules in the research and development pipeline possess poor aqueous solubility and, hence, are not suitable for further development. Therefore, the pharmaceutical industry is continuously in search of techniques to tackle the issue of poor solubility. Cocrystallization has gained popularity as one such technique for the modulation of physicochemical properties of an active pharmaceutical ingredient (API). Pharmaceutical cocrystals consist of an API non-covalently linked to a crystal former or coformer that plays an important role in imparting the desired properties to the cocrystal. Cocrystallization of an API with a suitable coformer not only enhances solubility but also helps in improving physicochemical properties such as stability, bioavailability, mechanical properties, etc., without changing the pharmacological activity of the API. The past decade has experienced enormous growth in cocrystal research which paved the way for drug-drug, higherorder, and nano-sized cocrystals, and further exploration of the applications of cocrystals is still going on. Recently FDA and EMA have released regulatory guidelines for pharmaceutical cocrystals, which grant them a status similar to that of polymorphs and salts, which in turn opens a wider prospect for pharmaceutical cocrystals in terms of intellectual property.

Solubility and Preferential Solvation of Caffeine and Theophylline in {Methanol + Water} Mixtures at 298.15 K

Solubility is a very important property of drugs involved in purification processes and the different pharmaceutical dosage form design stages. Otherwise, caffeine and theophylline are alkaloid drugs widely used in several solid and liquid pharmaceutical formulations. The equilibrium solubility of caffeine and theophylline were determined in {methanol + water} binary mixtures at 298.15 K by means of the shaken flask method and both mass balance and UV spectrophotometric composition analyses. Solubility is expressed in both molarity and mole fraction. Maximum solubility of both drugs is observed in a mixture of similar proportions of methanol and water instead of the neat cosolvent. All these solubility values were correlated with the Jouyban–Acree model. Preferential solvation parameters by methanol (δx 1,3) of these xanthines were derived from their thermodynamic solution properties by using the inverse Kirkwood–Buff integrals method. For both compounds the δx 1,3 values are negative in water-rich and methanol-rich mixtures but positive in mixtures with almost the same proportion of methanol and water. It is conjectured that in the former case the hydrophobic hydration around non-polar groups of these drugs plays a relevant role in the solvation. Besides, the preferential solvation of these solutes by methanol in mixtures of similar cosolvent compositions could be explained in terms of the higher basicity of methanol compared to water. Finally, the preferential solvation by water in methanol-rich mixtures could be a consequence of the higher acidity of water compared to methanol.

Computer Optimization of Biodegradable Nanoparticles Fabricated by Dispersion Polymerization.

Quality by design (QbD) in the pharmaceutical industry involves designing and developing drug formulations and manufacturing processes which ensure predefined drug product specifications. QbD helps to understand how process and formulation variables affect product characteristics and subsequent optimization of these variables vis-à-vis final specifications. Statistical design of experiments (DoE) identifies important parameters in a pharmaceutical dosage form design followed by optimizing the parameters with respect to certain specifications. DoE establishes in mathematical form the relationships between critical process parameters together with critical material attributes and critical quality attributes. We focused on the fabrication of biodegradable nanoparticles by dispersion polymerization. Aided by a statistical software, d-optimal mixture design was used to vary the components (crosslinker, initiator, stabilizer, and macromonomers) to obtain twenty nanoparticle formulations (PLLA-based nanoparticles) and thirty formulations (poly-ɛ-caprolactone-based nanoparticles). Scheffe polynomial models were generated to predict particle size (nm), zeta potential, and yield (%) as functions of the composition of the formulations. Simultaneous optimizations were carried out on the response variables. Solutions were returned from simultaneous optimization of the response variables for component combinations to (1) minimize nanoparticle size; (2) maximize the surface negative zeta potential; and (3) maximize percent yield to make the nanoparticle fabrication an economic proposition.

Evaluation of sodium alginate as drug release modifier in matrix tablets

Alginates are useful natural polymers suitable for use in the design of pharmaceutical dosage forms. However, the effects of particle size, viscosity and chemical composition of alginates on drug release from alginate matrix tablets are not clearly understood. Hence, 17 grades of sodium alginate with different particle size distributions, viscosities and chemical compositions were used to prepare matrix tablets at various concentrations to screen the factors influencing drug release from such matrices. Particle size was found to have an influence on drug release from these matrices. Sodium alginate was subsequently classified into several size fractions and also cryogenically milled to produce smaller particle size samples. Cryogenic milling could be successfully applied to pulverize coarse alginate particles without changing the quality through degradation or segregation. This study showed the significance of each alginate property in modulating drug release: particle size is important in initial alginic acid gel barrier formation as it affected the extent of burst release; higher alginate viscosity slowed down drug release rate in the buffer phase but enhanced release rate in the acid phase; high M-alginate might be more advantageous than high-G-alginate in sustaining drug release; and, the effect of increasing alginate concentration was greater with larger alginate particles. This can serve as a framework for formulators working with alginates. Furthermore, the results showed that sodium alginate matrices can sustain drug release for at least 8 h, even for a highly water-soluble drug in the presence of a water-soluble excipient.

Solute and solvent effects on the thermorheological properties of poly(oxyethylene)–poly(oxypropylene) block copolymers: Implications for pharmaceutical dosage form design

AbstractDespite their widespread use as platforms for topical drug delivery systems, there is a relative lack of information concerning the thermorheological and viscoelastic properties of poloxamer systems and the effects of formulation components on these properties. To address this deficit, we examined the effects of the poloxamer concentration (25 and 35% w/w), molecular weight blend (poloxamer 407 and poloxamer 188), cosolvents (ethanol, propylene glycol, and glycerol), and presence of inorganic and organic electrolytes (sodium chloride and tetracaine hydrochloride, respectively) on these properties. The rheological properties were examined with a rheometer (4‐cm‐diameter, stainless steel, parallel‐plate geometry) in either thermal sweep (0.5 Hz) or frequency sweep (0.01–1.0 Hz and 37°C) modes. Increasing the poloxamer concentration increased the elasticity [i.e., increased the storage modulus (G′) and reduced the loss tangent (tan δ)] and reduced the sol–gel transition temperature (Tm) of all the formulations. Decreasing the ratio (407:188) increased Tm and reduced the elasticity of all the formulations. Increasing the concentration of ethanol, propylene glycol, or glycerol in the solvent reduced Tm. The presence of ethanol reduced G′ and increased tan δ in a concentration‐dependent fashion, whereas the viscoelastic properties of the poloxamers were more tolerant of glycerol (in particular) and propylene glycol. The elasticity of the formulations containing up to 10% glycerol and 5% propylene glycol was increased with respect to their aqueous counterparts. The presence of sodium chloride reduced Tm and, at lower concentrations (1 and 3%), increased G′ and reduced tan δ for aqueous poloxamer systems. Conversely, the addition of a model therapeutic agent, tetracaine hydrochloride (5 and 7% w/w), significantly increased Tm and altered the viscoelastic character of the poloxamer system, notably reducing G′ and increasing the loss modulus and tan δ. Alterations in the viscoelastic and thermorheological properties of aqueous poloxamer systems will have implications for their clinical performance. This study, therefore, has highlighted the need for the rational selection of components in the formulation of poloxamer systems as platforms for topical drug delivery. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 87: 1016–1026, 2003

Influence of two different types of excipient on drug percolation threshold

The application of the principles of percolation theory is providing a more rational pharmaceutical dosage form design. The drug percolation threshold is the parameter that provides a better description of the system according to this theory. In order to check the possibility of use the drug percolation threshold as a preformulation parameter, the influence of the main formulation factors is being studied. The aim of this work is to study the influence of the type of excipient on the drug percolation threshold. For this purpose, two excipients exhibiting very different mechanical behaviour have been selected. Inert matrices were prepared using Ethocel® 100 and Eudragit® RS-PM as excipients and KCl as a model drug. Release assays were performed using the rotating disk method. The drug percolation threshold was estimated employing the method of Leuenberger and Bonny. The following confidence intervals (95%) were obtained: ϵ c=0.3644±0.0641 and ϵ c=0.3407±0.0345 of total porosity for matrices containing Eudragit® RS-PM and Ethocel® 100, respectively. On the light of the obtained results, no significant differences were found on the drug percolation thresholds for two excipients having very different mechanical behaviour.

Application of Percolation Theory to Characterize the Release Behavior of Carteolol Matrix Systems

The paper reports a study of the capability of the percolation theory to explain the influence of several formulation factors over the release behavior of carteolot hydrochloride inert matrix systems. For this purpose, previously prepared matrix systems have been employed. The characterization of these matrices by means of “classical theories” has been reported in previous papers. Similar percolation thresholds have been found (52.7%, 56.2% v/v for the insoluble phase and 48.2% to 51.2% v/v for the soluble phase), even with changing formulation factors such as nature and percentage of polymer, type of wetting liquid and nature, and percentage of filler. This fact suggests an advantage for the application of percolation theory to the rationalization of pharmaceutical dosage form design. From the obtained results, the characterization of a multicomponent system on the basis of percolation theory seems to be rather general. On the other hand, the relatively high percolation thresholh obtained can be attributed to the different particle sizes of the components according to correlated percolation models

Polymer–Drug Interacted Systems in the Physicochemical Design of Pharmaceutical Dosage Forms I: Drug Salts with PVM/MA and with a PVM/MA Hemi-Ester

The applicability of a polymer-drug interacted system in the physicochemical design of pharmaceutical dosage forms has been investigated. Salts of poly(methyl vinyl ether/maleic anhydride) and methapyrilene base were prepared. In vitro release patterns were determined by an equilibrium dialysis procedure. Dialytic release rates of the polymer-drug salt in solution demonstrated no appreciable difference in drug availability with respect to the free drug or its hydrochloride salt. In vitro dissolution rates of the polymer-drug salt in solid form showed similar results. Polymer-drug salts formed with the 1,12-dihydroxyoctadecane hemi-ester of poly-(methyl vinyl ether/maleic anhydride) exhibited prolongation of the release of the drug from granular and tableted forms in vitro.