Excipient System Research Articles

Density Functional Theory Interaction Study of a Polyethylene Glycol-Based Nanocomposite with Cephalexin Drug for the Elimination of Wound Infection.

In this paper, density functional theory (DFT) simulations are used to evaluate the possible use of a graphene oxide-based poly(ethylene glycol) (GO/PEG) nanocomposite as a drug delivery substrate for cephalexin (CEX), an antibiotic drug employed to treat wound infection. First, the stable configuration of the PEGylated system was generated with a binding energy of −25.67 kcal/mol at 1.62 Å through Monte Carlo simulation and DFT calculation for a favorable adsorption site. The most stable configuration shows that PEG interacts with GO through hydrogen bonding of the oxygen atom on the hydroxyl group of PEG with the hydrogen atom of the carboxylic group on GO. Similarly, for the interaction of the CEX drug with the GO/PEG nanocomposite excipient system, the adsorption energies are computed after determining the optimal and thermodynamically favorable configuration. The nitrogen atom from the amine group of the drug binds with a hydrogen atom from the carboxylic group of the GO/PEG nanocomposite at 1.75 Å, with an adsorption energy of −36.17 kcal/mol, in the most stable drug–excipient system. Drug release for tissue regeneration at the predicted target cell is more rapid in moist conditions than in the gas phase. The solubility of the suggested drug in the aqueous media around the open wound is shown by the magnitude of the predicted solvation energy. The findings from this study theoretically validate the potential use of a GO/PEG nanocomposite for wound treatment application as a drug carrier for sustained release of the CEX drug.

Formulation of spray dried enzymes for dry powder inhalers: An integrated methodology

One of the main challenges when developing a spray dried formulation of an inhalable enzyme is the generation of a safe and effective aerosol, able to reach the lungs, while preserving protein function and structural levels of the biologic. Hence, an appropriate excipient selection based on enzyme stabilization, inhalation precedence and spray drying (SD) process development is required to meet this balance. Herein, an integrated methodology is presented to expedite the selection of the best dry powder inhaler excipient system to formulate three model enzymes of increasing molecular mass and structural complexity belonging to the oxidoreductase class and often implicated in oxidative stress: superoxide dismutase, glucose oxidase and catalase. Three non-reducing sugars and four amino acids were screened using High Throughput Isothermal Denaturation Fluorimetry (HT-ITDF) for a stabilizing effect on the enzymes quaternary structure. For each tested enzyme, the sugar and amino acid showcasing a stabilizing effect, were spray dried together at fixed process conditions for three different ratios, to assess which formulation would then display the best aerodynamic performance. After SD, using the selected conditions, all powders displayed 65–85% of fine particle fraction (FPF) whilst each enzyme kept the oligomeric state. The present integrated methodology proved to be successful, allowing to narrow down 36 potential formulations (three sugars × four amino acids × three ratios) to only one for each enzyme, within few hours, while requiring a μg range of sample amount.

Evaluation of the stability of a spray-dried tuberculosis vaccine candidate designed for dry powder respiratory delivery

Particle engineering via spray drying was used to develop a dry powder presentation of an adjuvanted tuberculosis vaccine candidate. This presentation utilizing a trileucine-trehalose excipient system was designed to be both thermostable and suitable for respiratory delivery. The stability of the spray-dried vaccine powder was assessed over one year at various storage temperatures (-20, 5, 25, 40, 50 °C) in terms of powder stability, adjuvant stability, and antigen stability. A formulation without trileucine was included as a control. The results showed that the interior particle structure and exterior particle morphology of the powder was maintained for one year at 40 °C, while the control case exhibited a small extent of particle fusing under the same storage conditions. Moisture content was maintained, and powder solid state remained amorphous for all storage temperatures. Aerosol performance was assessed with a commercial dry powder inhaler in combination with a human mouth-throat model. The emitted dose and lung dose were maintained for all samples after one year at temperatures up to 40 °C. Nanoemulsion size and oil content of the adjuvant system were maintained after one year at temperatures up to 40 °C, and the agonist content was maintained after one year at temperatures up to 25 °C. The antigen was completely degraded in the control formulation at seven months of storage at 40 °C; by contrast, 45% of the antigen was still present in the trehalose-trileucine formulation after one year of storage at 50 °C. Comparatively, the antigen was completely degraded in a liquid sample of the vaccine candidate after only one month of storage at 37 °C. The spray-dried trehalose-trileucine vaccine powder clearly maintained its inhalable properties after one year’s storage at high temperatures and improved overall thermostability of the vaccine.

Chitosan based co-processed excipient for improved tableting

Chitosan is a multipurpose polymer with immense utility in pharmaceutical drug delivery systems. Low density, poor flowability and inadequate compression characteristics have limited its use as a tablet excipient. To address these limitations, a new tri-component excipient system composed of chitosan, mannitol and crospovidone was developed using spray drying technique. Mannitol was utilized for its ability to act as a bulking agent and to harness its unique characteristics such as a low hygroscopicity, strong inertness towards other excipients, whereas crospovidone was used as the disintegrant. Central composite response surface model was employed to obtain optimum combination of these components. Resulting coprocessed excipient showed remarkable improvement in density and flowability as confirmed by SeDeM diagram expert system. Heckel and Kawakita analysis predicted superior compression features of developed excipient for tableting. Furthermore, the applicability of developed excipient was studied by formulating paracetamol tablet as a model formulation by direct compression. Co-process excipient consisting of 50% chitosan, 43% mannitol and 6.5% crospovidone provided tablets with desired hardness of 100 N having disintegration time less than 25 s. Therefore, developed multifunctional coprocessed excipient exhibited promising results with potential for scale up and wide applicability in drug delivery.

Studies on effect of co-processing on palmyrah and maize starch mixtures using DOE approach

Starch mixture is an important approach in designing drug delivery system with modulated properties. The aim of the present work is to study the effect of pregelatinization on starch mixture by varying the concentration of palmyrah and maize starch. All the starch mixtures were statistically designed using 32 full factorial design. Further, the mixtures were characterized for physicochemical and drug release properties. The amylose content, water holding capacity (WHC), swelling and solubility power tend to increase with increase in pregelatinization time. The X-ray diffractogram (XRD) confirmed the reduction in crystallinity of starch mixture with increase in pregelatinization time. The FT-IR study confirmed the gelatinization characteristics of the mixture. All the pregelatinized starch mixture exhibited shear-thinning behavior. Micromeritic property of various starch mixture showed the good flow properties. Formulation with this novel excipient system, using paracetamol as model drug indicated its utility for immediate release dosage form.

Preparation and evaluation of diclofenac sodium orally disintegrating tablets

Abstract Orally disintegrating tablets (ODTs) are dosage forms which disintegrate in mouth within seconds without need of water. This type of quality in dosage form can be attained by addition of different varieties of excipients. Pharmaburst™ 500 is a co-processed excipient system which allows rapid disintegration and low adhesion to punches. The aim of the present study was to develop and evaluate 25 mg diclofenac sodium ODTs (orodispersible tablets) batches by direct compression method at different compression forces 10 kN (F1) and 20 kN (F2) and directly compressible excipients used in different ratio (Avicel PH 102, magnesium stearate and coprocessed excipient Pharmaburst™ 500, 70% and 80% w/w). The obtained batches were analyzed for appearance, tablet thickness, uniformity of weight, hardness, friability, disintegration time, and non-compendial methods (wetting time). Co-processed Pharmaburst™ 500 excipient 70% used for sodium diclofenac ODT obtaining determined good results for quality control tests evaluation.

Optimized Formulation of a Thermostable Spray-Dried Virus-Like Particle Vaccine against Human Papillomavirus.

Existing vaccines against human papillomavirus (HPV) require continuous cold-chain storage. Previously, we developed a bacteriophage virus-like particle (VLP)-based vaccine for HPV infection, which elicits broadly neutralizing antibodies against diverse HPV types. Here, we formulated these VLPs into a thermostable dry powder using a multicomponent excipient system and by optimizing the spray-drying parameters using a half-factorial design approach. Dry-powder VLPs were stable after spray drying and after long-term storage at elevated temperatures. Immunization of mice with a single dose of reconstituted dry-powder VLPs that were stored at 37 °C for more than a year elicited high anti-L2 IgG antibody titers. Spray-dried thermostable, broadly protective L2 bacteriophage VLPs vaccine could be accessible to remote regions of the world (where ∼84% of cervical cancer patients reside) by eliminating the cold-chain requirement during transportation and storage.

The Influence of the API Properties on the ODTs Manufacturing from Co-processed Excipient Systems

Directly compressible co-processed excipient systems facilitate orodispersible tablets (ODTs) manufacturing. Despite several excipient systems available, it is reported that the incorporation of high drug dose into the tablet mass may negatively affect both disintegration and mechanical properties. Therefore the influence of drug properties on the quality of orodispersible tablets was investigated. Fast dissolving tablet matrix was made of a co-processed excipient system F-Melt. Two grades of F-Melt that differed in composition, particle shape, and specific surface area were used to form tablet matrix. Ibuprofen, diclofenac sodium, and diltiazem hydrochloride were chosen as model drugs of different physicochemical properties such as solubility, particle size, and shape. Ninety formulations containing 12.5, 25, or 50wt% of the model drug and F-Melt type C or M were prepared by direct compression. The quality of tablets was examined on the base of disintegration time, wetting time, mechanical resistance and texture analysis. The results showed that F-Melt grade, drug solubility, and its dose had an influence on the quality of tablets. From ninety formulations prepared, only four batches containing F-Melt type C and 12.5wt% of ibuprofen, diclofenac sodium, or diltiazem hydrochloride could be classified as ODTs. Their disintegration time ranged from 41 to 144s. In the case of F-Melt type M, tablets disintegrating within 101s of friability below 1% could be prepared only if 12.5wt% of diclofenac sodium was incorporated into the tablet mass.

A novel multifunctional pharmaceutical excipient: Modification of the permeability of starch by processing with magnesium silicate

A directly compressible excipient has been developed by co-processing starch with magnesium silicate. The foregoing was achieved either by co-precipitation of magnesium silicate onto different types of starch or by dry granulation of maize starch with magnesium silicate. A variety of techniques (permeability, water retention/swelling, compression analysis, scanning electron microscopy, tensile strength and disintegration/dissolution studies) were used to characterize these systems. The permeability of the formulations produced using the two methods was evaluated experimentally using Darcy's permeability law. Magnesium silicate, as an anti-adhering agent, increases the permeability of both maize and partially pregelatinized starch, resulting in compacts of high mechanical strength, short disintegration time and low lubricant sensitivity. Such advantages are evident when the properties of the physical mixture of maize starch with magnesium silicate are compared with the co-precipitation and dry granulation techniques. Formulation with this novel excipient system, using paracetamol as a model drug, indicated its suitability as a single multifunctional excipient.

Optimization of a pharmaceutical freeze-dried product and its process using an experimental design approach and innovative process analyzers

The aim of the present study was to examine the possibilities/advantages of using recently introduced in-line spectroscopic process analyzers (Raman, NIR and plasma emission spectroscopy), within well-designed experiments, for the optimization of a pharmaceutical formulation and its freeze-drying process. The formulation under investigation was a mannitol (crystalline bulking agent)–sucrose (lyo- and cryoprotector) excipient system. The effects of two formulation variables (mannitol/sucrose ratio and amount of NaCl) and three process variables (freezing rate, annealing temperature and secondary drying temperature) upon several critical process and product responses (onset and duration of ice crystallization, onset and duration of mannitol crystallization, duration of primary drying, residual moisture content and amount of mannitol hemi-hydrate in end product) were examined using a design of experiments (DOE) methodology. A 2-level fractional factorial design (25−1=16 experiments+3 center points=19 experiments) was employed. All experiments were monitored in-line using Raman, NIR and plasma emission spectroscopy, which supply continuous process and product information during freeze-drying. Off-line X-ray powder diffraction analysis and Karl-Fisher titration were performed to determine the morphology and residual moisture content of the end product, respectively.In first instance, the results showed that – besides the previous described findings in De Beer et al., Anal. Chem. 81 (2009) 7639–7649 – Raman and NIR spectroscopy are able to monitor the product behavior throughout the complete annealing step during freeze-drying. The DOE approach allowed predicting the optimum combination of process and formulation parameters leading to the desired responses. Applying a mannitol/sucrose ratio of 4, without adding NaCl and processing the formulation without an annealing step, using a freezing rate of 0.9°C/min and a secondary drying temperature of 40°C resulted in efficient freeze-drying supplying end products with a residual moisture content below 2% and a mannitol hemi-hydrate content below 20%. Finally, using Monte Carlo simulations it became possible to determine how varying the factor settings around their optimum still leads to fulfilled response criteria, herewith having an idea about the probability to exceed the acceptable response limits. This multi-dimensional combination and interaction of input variables (factor ranges) leading to acceptable response criteria with an acceptable probability reflects the process design space.

Crystallization of Glycine During Freezing of a 40/60 w/w Sucrose/Glycine Excipient System: An Alternative to the Johnson–Mehl–Avrami (JMA) Equation for Modeling Dispersive Kinetics

The isothermal crystallization of glycine in a 40/60 (w/w) sucrose/glycine excipient system is examined with the goal of comparing the kinetic information obtained by using the Johnson-Mehl-Avrami (JMA) equation with that collected using a novel, dispersive kinetic model equation recently proposed by the author. It is found that while both models explain the experimental data reasonably well, the latter equation fits the data, collected at temperatures in the range 241-251 K, without the use of empirical parameters. The values of the activation energy and Arrhenius constant (frequency factor) for both models agree within experimental error.

Development of a multi particulate extended release formulation for ZK 811 752, a weakly basic drug

ZK 811 752, a potent candidate for the treatment of autoimmune diseases, demonstrated pH-dependent solubility. The resulting release from conventional mini matrix tablets decreased with increasing pH-values of the dissolution medium. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Mini matrix tablets were prepared by direct compression of drug, matrix former (polyvinylacetate/polyvinylpyrrolidone; Kollidon ® SR) and excipients (lactose, calcium phosphate or maize starch). To solve the problem of pH-dependent solubility fumaric acid was added to the drug–polymer excipient system. The addition of fumaric acid was found to maintain low pH-values within the mini tablets during release of ZK 811 752 in phosphate buffer pH 6.8. Thus, micro environmental conditions for the dissolution of the weakly basic drug were kept constant and drug release was demonstrated to be pH-independent. Incorporation of water-soluble (lactose) or highly swellable (maize starch) excipients accelerated drug release in a more pronounced manner compared to the water-insoluble excipient calcium phosphate. Stability studies demonstrated no degradation of the drug substance and reproducible drug release patterns for mini matrix tablets stored at 25 °C/60% RH and 30 °C/70% RH for up to 6 months.

Freeze-drying of proteins from a sucrose-glycine excipient system: Effect of formulation composition on the initial recovery of protein activity

The purpose of this study was to investigate the effect of sucrose-glycine excipient systems on the stability of selected model proteins during lyophilization. Recovery of protein activity after freeze-drying was examined for the model proteins lactate dehydrogenase and glucose 6-phosphate dehydrogenase in a sucrose-glycine-based excipient system in which the formulation composition was systematically varied. In a sucrose-only excipient system, activity recovery of both model proteins is about 80% and is independent of sucrose concentration over a range from 1 to 40 mg/mL. When both sucrose and glycine are used and the ratio of the 2 excipients is varied, however, activity recovery decreases in a pattern that is consistent with the inhibition of activity recovery by glycine crystals, despite the presence of an adequate amount of sucrose to afford protection. Annealing of sucrose-glycine formulations causes a small but significant decrease in activity recovery relative to unannealed controls, whereas no annealing effect is observed with sucrose-only formulations. Addition of 0.01% polysorbate 80 to the formulation resulted in complete recovery of activity, irrespective of the sucrose-glycine ratio or annealing. Addition of the same concentration of polysorbate 80 to the reconstitution medium caused an increase in activity recovery for each formulation, but the overall pattern remained unchanged. The data are consistent with an interfacial model for lyophilization-associated loss of protein activity involving denaturation at a solid/freeze-concentrate interface.

Kinetics of glycine crystallization during freezing of sucrose/glycine excipient systems

Isothermal calorimetry and low‐field nuclear magnetic resonance were used to measure crystallization of glycine during annealing of glycine/sucrose mixtures, a commonly‐used excipient system for freeze‐dried proteins. Kinetics of crystallization of glycine were consistent between the two methods, although the NMR method was significantly more sensitive. By the calorimetric method used here, sensitivity was lost when the total solute concentration was below about 20% (w/v) and the relative glycine concentration below about 35% of the total solids. By the NMR method, total solute concentrations as low as 5% (w/v) could be studied. When the relative concentration of glycine is below about 30% of total solids, the time course of crystallization becomes excessively long for practical freeze‐drying applications. A good fit of the crystallization data was obtained with the Johnson–Mehl–Avrami (JMA) equation. The Avrami exponent of 2.5 is consistent with diffusion‐limited spherulitic growth of glycine. © 2005 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:625–631, 2005

Obtaining higher transesterification rates with subtilisin Carlsberg in nonaqueous media

Three phase partitioning (protein precipitate obtained as an interfacial layer between lower aqueous and upper t-butanol phases, formed by the addition of ammonium sulphate and t-butanol to the aqueous solution of protein) followed by lyophilization in the presence of two-component excipient resulted in 400–480× increases in transesterification activity of lyophilized powders of subtilisin Carlsberg, depending on the solvent. The three phase partitioned enzyme, ‘dried’ by washing with butanol, gave 3–4× higher rates (depending on the solvent used) than the enzyme preparation dried by lyophilization in the presence of two-component excipient system.

Physico-Chemical Characterization of Drugs and Drug Forms in the Solid State

This review addresses the general problem of the physico-chemical characterization of drugs and drug products. The characterization may be performed with a range of methods that appears to be mostly limited by imagination, and aims to fulfill one or more of the following goals: gather data relevant in predicting / optimizing performances of a drug, selecting its delivery system, planning a scaled-up production and associated quality controls, complying with regulations. In keeping with the general focus of the Journal, most examples presented will deal with antinfective agents, although the physico-chemical characterization is largely independent of the therapeutic goal. We begin by reviewing the substantial and recent advances in new classes of materials for drug delivery and in techniques for experimental and theoretical studies of physico-chemical properties of pharmaceutical compounds. We then introduce through examples the complex phenomenology of these properties, which may be investigated also with standard and inexpensive experimental techniques. The last part of the review addresses the problem of defining a fast and reliable protocol for investigating drug-excipient compatibility problems. Keywords: physico-chemical characterization, drugs, scaled-up production, drug-excipient compatibility, drug, &, excipient system

Scale-up Feasibility in High-Shear Mixers: Determination Through Statistical Procedures

The wet granulation scale-up of a formulation exhibiting plastic deformation behavior under compression was examined. Through experimental factorial design, the effect of solution level, mixing time, and mixer speed on granulation properties was investigated. Measurements of mean particle size, tapped density, bulk density, Carr's index, coarse-to-fine ratio, cumulative percentage, and flow rate were taken and compared among granulations. In addition, comparisons were done on the hardness of tablets made from the formulations. It was shown that the characteristics of the granulations made under different conditions were highly reproducible. The excipient system of microcrystalline cellulose and pregel starch was shown to be a very robust formulation that is resistant to changes in the scaling-up process in high-shear mixers.

The effects of formulation variables on the stability of freeze-dried human growth hormone.

Formulation often has a dramatic effect on degradation of proteins during the freeze-drying process as well as impacting on the "shelf-life" stability of the freeze-dried product. This research presents the results of a formulation optimization study of the "in-process" and shelf-life stability of freeze-dried human growth hormone (hGH). Chemical decomposition via methionine oxidation and deamidation of asparagine residues as well as irreversible aggregation were characterized by HPLC assay methodology. In-process degradation and stability of low moisture freeze-dried solids were studied at 25 and 40 degrees C in a nominal nitrogen headspace (approximately 0.5% O2). Formulation variables included pH, level of salts, and the nature of the lyoprotectant. Studies of the effect of shear on aggregation in solutions indicated that shear comparable to that experienced during filtration does not induce aggregation. Irreversible changes in hGH during the freeze-drying process were minimal, but chemical decomposition via methionine oxidation and asparagine deamidation and aggregation did occur on storage of the freeze-dried solid. Decomposition via methionine oxidation was significant. A combination of mannitol and glycine, where the glycine remains amorphous, provided the greatest protection against decomposition and aggregation. It is postulated that an excipient system that remains at least partially amorphous is necessary for stabilization. However, the observation that dextran 40 formulations showed poor stability toward aggregation demonstrates that an amorphous excipient system is not a sufficient condition for stability. Stability of the solid was optimal when produced from solutions in the pH range, 7-7.5, with severe aggregation being observed at high pH. The level of sodium phosphate buffer affected stability of the solid, although this relationship was complex. Freeze-drying in the presence of NaCl produced severe aggregation and precipitation during the freeze-drying process as well as acceleration of oxidation and/or deamidation.