Controlling drug delivery from polymer microspheres by exploiting the complex interrelationship of excipient and drug crystallization

Semicrystalline polymers are often used as macromolecular excipients in active pharmaceutical ingredient (API)-delivery systems. In such systems, the morphological structure and crystalline characteristics of the excipient have a direct impact upon the drug-delivery rate. In this study, polycaprolactone (PCL)-based microspheres prepared via melt-printing were loaded with 10, 30, and 50% ibuprofen (IBU). In vitro release studies showed that, for a constant amount of IBU, the API was released fastest from the 30%-loaded microspheres, followed by the 50%- and 10%-loaded microspheres. The discrepancy in these release rates was investigated using scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, and thermodynamic analyses, revealing the complex morphological and crystalline interrelationships of PCL and IBU. Although it is generally accepted that the degree of crystallinity of the excipient is the main factor controlling the release of the API, we found that the crystallite size of the small-molecule API is of primary importance. Moreover, these factors, which are controllable via the parameters used in melt-based preparation, can be exploited to tune drug-release rates. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47227.     

Ibuprofen grafted on poly(2-hydroxyethylmethacrylate): Synthesis,mass transfer,and in vitro drug release investigations

Poly(2-hydroxyethylmethacrylate-graft-ibuprofen) (IpGH) of different ibuprofen (Ibu) contents was prepared by grafting of Ibu groups on poly(2-hydroxyethyl methacrylate) (PHEMA) in an esterification reaction route. The resulted copolymers were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance, differential scanning calorimetry, thermal gravimetric analysis, X-ray diffraction, and scanning electron microscope analysis. The cytotoxicity test and the free radical scavenging ability of this material were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium (MTT) and 1,1-diphenyl-2-picryl-hydrazyl assay methods, respectively. The in vitro release study of Ibu through a retro-esterification reaction of IpHG material during 3 days reveals that the release dynamic depends on the initial Ibu grafted, pH media, and the swelling degree of PHEMA. It was also revealed that the water solubility of Ibu easily reached a maximum of 0.216?mg?mL^?1. The diffusion of Ibu through the polymer matrix obeys the Fickian model. The estimated distribution of the cumulative drug released in different simulated digestive organs reveals that the IpHG7 containing 6.69?mol% of Ibu content showed the best performance.     

Effects of humidity and surfaces on the melt crystallization of Ibuprofen

Melt crystallization of ibuprofen was studied to understand the effects of humidity and surfaces. The molecular self-assembly during the amorphous-to-crystal transformation was examined in terms of the nucleation and growth of the crystals. The crystallization was on Al, Au, and self-assembled monolayers with -CH(3), -OH, and -COOH functional groups. Effects of the humidity were studied at room temperature (18-20 °C) with relative humidity 33%, 75%, and 100%. Effects of the surfaces were observed at -20 °C (relative humidity 36%) to enable close monitoring with slower crystal growth. The nucleation time of ibuprofen was faster at high humidity conditions probably due to the local formation of the unfavorable ibuprofen melt/water interface. The crystal morphologies of ibuprofen were governed by the nature of the surfaces, and they could be associated with the growth kinetics by the Avrami equation. The current study demonstrated the effective control of the melt crystallization of ibuprofen through the melt/atmosphere and melt/surface interfaces.     

计算机模拟对嵌段共聚物胶束结构的优化设计

胶束对疏水性药物的增溶作用与药物和载体材料的相容性密切相关,本文通过热力学方法判断二者的相容性。以布洛芬作为模型药物,采用Materials Studio模拟软件计算一系列疏水链段与布洛芬的混合能Emix及混合自由能ΔGmix,筛选适合布洛芬的胶束疏水链段。结果显示布洛芬与聚丙烯、聚氧丙烯等疏水链段的混合自由能为正值,与聚乳酸/乙醇酸的的混合自由能为负值,根据混合自由能原理,文中所选的嵌段共聚物胶束的疏水链段中,聚乳酸/乙醇酸与布洛芬的相容性最好。     

Investigation of the potential for direct compaction of a fine ibuprofen powder dry-coated with magnesium stearate

Intensive dry powder coating (mechanofusion) with tablet lubricants has previously been shown to give substantial powder flow improvement. This study explores whether the mechanofusion of magnesium stearate (MgSt), on a fine drug powder can substantially improve flow, without preventing the powder from being directly compacted into tablets. A fine ibuprofen powder, which is both cohesive and possesses a low-melting point, was dry coated via mechanofusion with between 0.1% and 5% (w/w) MgSt. Traditional low-shear blending was also employed as a comparison. No significant difference in particle size or shape was measured following mechanofusion. For the low-shear blended powders, only marginal improvement in flowability was obtained. However, after mechanofusion, substantial improvements in the flow properties were demonstrated. Both XPS and ToF-SIMS demonstrated high degrees of a nano-scale coating coverage of MgSt on the particle surfaces from optimized mechanofusion. The study showed that robust tablets were produced from the selected mechanofused powders, at high-dose concentration and tablet tensile strength was further optimized via addition of a Polyvinylpyrrolidone (PVP) binder (10% w/w). The tablets with the mechanofused powder (with or without PVP) also exhibited significantly lower ejection stress than those made of the raw powder, demonstrating good lubrication. Surprisingly, the release rate of drug from the tablets made with the mechanofused powder was not retarded. This is the first study to demonstrate such a single-step dry coating of model drug with MgSt, with promising flow improvement, flow-aid and lubrication effects, tabletability and also non-inhibited dissolution rate.     

The formulation of optimal mixtures with generalized disjunctive programming: A solvent design case study

Systematic approaches for the design of mixtures, based on a computer‐aided mixture/blend design (CAM^bD) framework, have the potential to deliver better products and processes. In most existing methodologies the number of mixture ingredients is fixed (usually a binary mixture) and the identity of at least one compound is chosen from a given set of candidate molecules. A novel CAM^bD methodology is presented for formulating the general mixture design problem where the number, identity and composition of mixture constituents are optimized simultaneously. To this end, generalized disjunctive programming is integrated into the CAM^bD framework to formulate the discrete choices. This generic methodology is applied to a case study to find an optimal solvent mixture that maximizes the solubility of ibuprofen. The best performance in this case study is obtained with a solvent mixture, showing the benefit of using mixtures instead of pure solvents to attain enhanced behavior. © 2016 The Authors AIChE Journal published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers AIChE J, 62: 1616–1633, 2016     

Synthesis of Spongy-Like Mesoporous Hydroxyapatite from Raw Waste Eggshells for Enhanced Dissolution of Ibuprofen Loaded via Supercritical CO2

The use of cheaper and recyclable biomaterials (like eggshells) to synthesize high purity hydroxyapatite (HAp) with better properties (small particle size, large surface area and pore volume) for applications (in environmental remediation, bone augmentation and replacement, and drug delivery systems) is vital since high-purity synthetic calcium sources are expensive. In this work, pure and mesoporous HAp nanopowder with large pore volume (1.4 cm³/g) and surface area (284.1 m²/g) was produced from raw eggshells at room temperature using a simple two-step procedure. The control of precursor droplets could stabilize the pH value of the reaction solution, because of the size of the needle (of the syringe pump used for precursor additions) leading to production of HAp with high surface area and pore size. The as-produced HAp revealed high ibuprofen (as a model drug) loading (1.38 g/g HAp), enhanced dissolution and controllable release of the drug via solute-saturated supercritical carbon dioxide.     

酰氯法制备布洛芬-聚乙二醇酯

分别用氯化亚砜（方法1）、草酰氯（方法2）两种方法将布洛芬[2-（4-异丁基苯基）丙酸]活化成2-（4-异丁基苯基）丙酰氯（Ⅰ）,再与聚乙二醇（PEG）的端羟基反应生成PEG修饰的布洛芬-聚乙二醇酯,即2-（4-异丁基苯基）丙酸-聚乙二醇酯（Ⅱ）。分别用核磁共振（1H-NMR）、红外光谱（IR）和凝胶渗透色谱（GPC）...     

运用手性固定相研究外消旋布洛芬的光学分离

Ibprofen is widely used as a non-steroidal anti-inflammatory drug and poduced as racemic mixture.Its pharmacological activity resides only is S-( )-enantiomer,and R-(-)-enantiomer is not only inactive but also has many side effects.Thus it is necessary to separate Renantiomer from racemic ibuprofen.We studied optical separation of racemic Ibuprofen with chiral high performance liquid chromatography(HPLC).,Out of three different chiral stationary phases,which were selected on the basis of structure and availability,two were found to be effective.There was optimum eluent composition for each stationary phase for good resolution in optical separation.Resolution decreased with increase of eluent flow rate,but effect of injection volume on resolution was insignificant at high eluent flow rate.     

Evaluation of various processes for simultaneous complexation and granulation to incorporate drug–cyclodextrin complexes into solid dosage forms

Insoluble drugs often formulated with various excipients to enhance the dissolution. Cyclodextrins (CDs) are widely used excipients to improve dissolution profile of poorly soluble drugs. Drug–CD complexation process is complex and often requires multiple processes to produce solid dosage form. Hence, this study explored commonly used granulation processes for simultaneous complexation and granulation. Poorly soluble drugs ibuprofen and glyburide were selected as experimental drugs. Co-evaporation of drug:CD mixture from a solvent followed by wet granulation with water was considered as standard process for comparison. Spray granulation and fluid bed processing (FBP) using drug:CD solution in ethanol were evaluated as an alternative processes. The dissolution data of glyburide tablets indicated that tablets produced by spray granulation, FBP and co-evaporation–granulation have almost identical dissolution profile in water and 0.1% SLS (>70% in water and >60% in SLS versus 30 and 34%, respectively for plain tablet, in 120?min). Similarly, ibuprofen:CD tablets produced by co-evaporation–granulation and FBP displayed similar dissolution profile in 0.01?M HCl (pH 2.0) and buffer pH 5.5 (>90 and 100% versus 44 and 80% respectively for plain tablets, 120?min). Results of this study demonstrated that spray granulation is simple and cost effective process for low dose poorly soluble drugs to incorporate drug:CD complex into solid dosage form, whereas FBP is suitable for poorly soluble drugs with moderate dose.