Improved dissolution behavior of lipophilic drugs by solid dispersions: the production process as starting point for formulation considerations

INTRODUCTION: Many new drug substances have low aqueous solubility which can cause poor bioavailability after oral administration. The application of solid dispersions is a useful method to increase the dissolution rate of these drugs and thereby improve their bioavailability. So far, several methods have been developed to prepare solid dispersions. To obtain a product with the desired attributes, both the formulation and production processes should be considered. AREAS COVERED: The most currently used methods to produce solid dispersions, such as the fusion method, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation, are reviewed in this paper. In addition, the physicochemical characteristics of the obtained solid dispersions are discussed. EXPERT OPINION: Solid dispersions can be successfully prepared by simple fusion, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation. Hot melt extrusion, spray drying and freeze drying are processes that can be applied for large scale production. The simple fusion method is not very suitable for large scale production, but is particularly suitable for screening formulations. The most recent method to produce sold dispersions is supercritical fluid precipitation. The process conditions of this method need extensive investigation, in particular in relationship with the selection of the type of carrier and/or solvent. Both processes and formulation aspects strongly affect the characteristics of solid dispersion products. Furthermore, application of crystalline solid dispersions is gaining increasing interest because they are thermodynamically more stable than amorphous solid dispersions.     

Enhanced dissolution rate of celecoxib using PVP and/or HPMC-based solid dispersions prepared by spray drying method

Celecoxib with low solubility and high permeability (BCS class II) in water is a non-steroidal anti-inflammatory drug used in the treatment of pain and inflammation, associated with rheumatoid arthritis, and several other inflammatory disorders. Also, it is a selective cyclooxygenase 2 inhibitor with low water solubility and high crystallinity. The objective of this study was to improve dissolution rate of celecoxib which was water-insoluble drug. Solid dispersions were prepared by spray drying as the solvent evaporation method. The dissolution behavior of solid dispersions was compared with Celebrex^® (Pfizer) as a control group in simulated gastric juice (pH 1.2, 0.5 % SLS. The characterization of the prepared solid dispersions is analyzed by scanning electron microscope, powder X-ray diffractometer, Fourier transform infrared spectroscopy and reverse phase-high performance liquid chromatography The best formulation was SD 8 in this study. It was the cumulative release of 97 % at 120 min. This study suggests that the solubility and bioavailability of poorly water-soluble celecoxib improved through the prepared solid dispersions by spray drying method.     

Single step bottom-up process to generate solid phospholipid nano-particles

Abstract

Context: The particularity of the Nano Spray Dryer B-90 is the nozzle containing a mesh vibrating at ultrasonic frequency.

Objective: To study process parameters and processability of crude phospholipid dispersions, in particular the effect of concentration and mesh aperture on both particle size of the dry solid phospholipid nano-particles and on the re-dispersed powder.

Materials and methods: Phospholipid dispersions containing trehalose as a stabilizer were spray dried. Particle size distributions of dry powders were evaluated by SEM micrographs and by PCS and cryo-TEM for the re-dispersed particles.

Results: Spray drying of crude liposome dispersions revealed solid phospholipid nano-particles. Aperture of nozzle mesh and concentration of the dispersions, respectively, both increased the size of solid phospholipid nano-particles. For crude dispersions, an upper limit with respect to processability was found close to below 10% (m/m) even if the crude dispersion was passed along the mesh several times; however, more effective dispersing methods such as pre-sonication can push the limit of processability to higher values.

Discussion and conclusion: The nano spray dryer is capable of spray drying crude dispersions of phospholipids in concentrations below 10% (m/m) generating solid phospholipid nano-particles relevant for pulmonary delivery. Re-dispersion of spray dried powder reveals liposomes.     

Fusion processing of itraconazole solid dispersions by kinetisol® dispersing: A comparative study to hot melt extrusion

KinetiSol® Dispersing (KSD) is a novel high energy manufacturing process investigated here for the production of pharmaceutical solid dispersions. Solid dispersions of itraconazole (ITZ) and hypromellose were produced by KSD and compared to identical formulations produced by hot melt extrusion (HME). Materials were characterized for solid state properties by modulated differential scanning calorimetry and X‐ray diffraction. Dissolution behavior was studied under supersaturated conditions. Oral bioavailability was determined using a Sprague–Dawley rat model. Results showed that KSD was able to produce amorphous solid dispersions in under 15 s while production by HME required over 300 s. Dispersions produced by KSD exhibited single phase solid state behavior indicated by a single glass transition temperature (T_g) whereas compositions produced by HME exhibited two T_gs. Increased dissolution rates for compositions manufactured by KSD were also observed compared to HME processed material. Near complete supersaturation was observed for solid dispersions produced by either manufacturing processes. Oral bioavailability from both processes showed enhanced AUC compared to crystalline ITZ. Based on the results presented from this study, KSD was shown to be a viable manufacturing process for the production of pharmaceutical solid dispersions, providing benefits over conventional techniques including: enhanced mixing for improved homogeneity and reduced processing times. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1239–1253, 2010     

Technology evaluation: Kollicoat IR

Introduction: Developments in industrial pharmacy are often linked to the discovery of pharmaceutical excipients. Although recently introduced as a material for immediate release coatings, Kollicoat IR already has other applications.

Areas covered: In this review, the different properties and pharmaceutical applications of Kollicoat IR as an excipient are discussed. In the first part, the chemical structure and the physicochemical characteristics are examined. The second part is a presentation of the available Kollicoat IR products followed by a brief overview of the preclinical studies completed for its use as an instant release coating material.

Expert opinion: Although the polymer was intended as an immediate release coating material for tablets, grafting PEG with polyvinyl alcohol to form this polymer provides physicochemical properties that lead to ever-broadening applications. Understanding its properties can lead to the development of a new use for Kollicoat IR. The addition of Kollicoat IR to an ethylcellulose or polyvinyl acetate tablet coat was successful at modifying the drug release rate. Designing a successful controlled release coat simply requires acknowledgment of the drug release mechanism from the mixture of polymers that includes Kollicoat IR. Moreover, the interaction between Kollicoat IR and poorly soluble drugs produces fast-dissolving solid dispersions prepared using hot stage extrusion, spray drying, or freeze drying.     

Producing Amorphous Solid Dispersions via Co-Precipitation and Spray Drying: Impact to Physicochemical and Biopharmaceutical Properties

Many small-molecule active pharmaceutical ingredients (APIs) exhibit low aqueous solubility and benefit from generation of amorphous dispersions of the API and polymer to improve their dissolution properties. Spray drying and hot-melt extrusion are 2 common methods to produce these dispersions; however, for some systems, these approaches may not be optimal, and it would be beneficial to have an alternative route. Herein, amorphous solid dispersions of compound A, a low-solubility weak acid, and copovidone were made by conventional spray drying and co-precipitation. The physicochemical properties of the 2 materials were assessed via X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, and scanning electron microscopy. The amorphous dispersions were then formulated and tableted, and the performance was assessed in vivo and in vitro. In human dissolution studies, the co-precipitation tablets had slightly slower dissolution than the spray-dried dispersion, but both reached full release of compound A. In canine in vitro dissolution studies, the tablets showed comparable dissolution profiles. Finally, canine pharmacokinetic studies showed that the materials had comparable values for the area under the curve, bioavailability, and C_max. Based on the summarized data, we conclude that for some APIs, co-precipitation is a viable alternative to spray drying to make solid amorphous dispersions while maintaining desirable physicochemical and biopharmaceutical characteristics.     

Confocal Raman-Spectroscopy: Analytical Approach to Solid Dispersions and Mapping of Drugs

Purpose. To compare the physical state of a drug in a liquid with a polymeric matrix. Methods. Solid solutions of ibuprofen in polyvinylpyrrolidone were obtained from the hot melt extrusion technique. In order to investigate the physicochemical stability, content, and homogeneity of the formulation, the tablets produced by a subsequent calendering step were examined using confocal Raman spectroscopy. In addition, a dimeric vinylpyrrolidone was synthesized and used to compare the physical state of embedding in a polymeric matrix with a physical solution of the active in a solvent, i.e. the dimeric vinylpyrrolidone. The spatial resolution of confocal Raman spectroscopy was used to image the drug distribution in the final form. Results. Confocal Raman spectroscopy has been successfully used to determine the state of ibuprofen in a solid matrix showing equivalence to a physical solution. Moreover, the physicochemical stability of the formulation under stress conditions and content, as well as homogeneity of drug distribution in the formulation matrix, has been examined with the same method, proving the efficiency of the approach. Conclusions. Confocal Raman spectroscopy offers a new approach for the analytical assessment of solid dispersions both covering the physical state as well as the distribution of the drug via its spatial resolution. Moreover, it is a promising tool for observing changes in a formulation due to physicochemical processes, e.g. recrystallisation and at the same time for locating the area where changes occur. Therefore, it may contribute to standard analytical methods to evaluate content and homogeneity.     

Microdialysis sampling and the clinical determination of topical dermal bioequivalence

The influence of the deposition pattern and spray characteristics of nasal powder formulations on the insulin bioavailability was investigated in rabbits. The formulations were prepared by freeze drying a dispersion containing a physical mixture of drum dried waxy maize starch (DDWM)/Carbopol^® 974P (90/10, w/w) or a spray-dried mixture of Amioca^® starch/Carbopol^® 974P (25/75, w/w). The deposition in the nasal cavity of rabbits and in a silicone human nose model after actuation of three nasal delivery devices (Monopowder, Pfeiffer and experimental system) was compared and related to the insulin bioavailability. Posterior deposition of the powder formulation in the nasal cavity lowered the insulin bioavailability.

To study the spray pattern, the shape and cross-section of the emitted powder cloud were analysed. It was concluded that the powder bulk density of the formulation influenced the spray pattern. Consequently, powders of different bulk density were prepared by changing the solid fraction of the freeze dried dispersion and by changing the freezing rate during freeze drying. After nasal delivery of these powder formulations no influence of the powder bulk density and of the spray pattern on the insulin bioavailability was observed.     

Solubility and dissolution rate enhancement of lumefantrine using hot melt extrusion technology with physicochemical characterisation

The interest in hot-melt extrusion as a drug delivery technology for the production of solid dispersion is growing rapidly. Lumefantrine (LUMF) is an antimalarial drug that exhibits poor oral bioavailability, in consequence of its poor aqueous solubility. To improve its antimalarial activity, solid dispersion formulation using hot melt extrusion technology was prepared. Appropriate selection of polymers, favoured the production of amorphous LUMF-polymer solid dispersions. The physicochemical properties of solid dispersions were characterized using scanning electron microscope, Infrared spectroscopy, differential scanning calorimetry and X-ray diffraction. LUMF SD showed enhanced dissolution rate attributed to amorphosization of LUMF. The IC50 value of LUMF SD formulations was found to be (0.084–0.213 ng/mL) i.e. 220–101 times lower than the IC50 value of pure LUMF (18.2 ng/mL) and 45–18 times lower than the IC50 value of standard antimalarial drug, chloroquine (3.8 ng/mL). Molecular dynamic simulation approach was used to investigate drug-polymer molecular interaction using computational modelling Schrodinger^® software. LUMF SD powder makes the Coartem^® therapy more operative with value-added beneficial comeback.     

Biopharmaceutical powders: particle formation and formulation considerations

It is well known that protein/peptide-based drug formulations are more stable in the solid state than in the liquid state, thereby offering stability advantages in ambient temperature storage, product shipping/distribution, and long-term shelf life. Novel powder-based drug delivery systems recently emerging for applications in sustained release, inhalation, intradermal delivery, etc, add more value to protein solid dosage forms. Despite great research interests in understanding the drying effects on protein stability and a large collection of publications focusing on this area, systematic accounts of powder formation techniques are lacking. This review is to summarize a number of methods currently available for protein powder preparation. Some are common methods such as lyophilization, spray drying, pulverization, and precipitation, and some methods are more recently developed such as supercritical fluid precipitation, spray-freeze drying, fluidized-bed spray coating and emulsion precipitation. In addition to examining the individual process effect on protein stability that is always the focus of formulation scientists, this review also likes to evaluate each method from a more practical sense in terms of process versatility and scalability. The conclusion is that each method has its own advantages and the use of a method is formulation and application specific. With the understanding of the principles and advantages of these methods, it can benefit our choice on selecting appropriate techniques for preparing a desired protein powder formulation for specific applications.     

Melt extrusion: from process to drug delivery technology.

Starting from the plastic industry, today melt extrusion has found its place in the array of pharmaceutical manufacturing operations. This article reviews the process technology with regard to the set up and specific elements of the extruder as well as its application. Melt extrusion processes are currently applied in the pharmaceutical field for the manufacture of a variety of dosage forms and formulations such as granules, pellets, tablets, suppositories, implants, stents, transdermal systems and ophthalmic inserts. As a specific area the manufacture of solid dispersions, in particular, solid molecular dispersions using the melt extrusion process is reviewed. Melt extrusion is considered to be an efficient technology in this field with particular advantages over solvent processes like co-precipitation. Potential drawbacks like the influence of heat stress and shear forces on the drug active have been overcome in a number of examples with drugs of different chemical structure. Examples of suitable excipients and recent findings like self-emulsifying preparations are presented. The article concludes with a number of published examples of melt extrudates applying the principle of solid molecular dispersions. Improved bioavailability was achieved again demonstrating the value of the technology as a drug delivery tool.     

Melt extrusion: process to product

Introduction: Niche applicability and industrial adaptability have led hot melt extrusion (HME) techniques to gain wide acceptance and have, therefore, solidified their place in the array of pharmaceutical research and manufacturing operations. Melt extrusion's momentum has resulted in extensive research publications, reviews and patents on the subject for over a decade. Currently, > 50% of the new drug candidates are speculated to be highly lipophilic and thus poorly bioavailable. HME is a key technology for these and other formulation and processing issues.

Areas covered: Various approaches have been addressed using HME in developing solid molecular dispersions and have demonstrated viability to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. This review provides a holistic perspective on HME from equipment, processing and materials to its varied applications in oral delivery (immediate release, sustained release, taste masking, enteric and targeted release, as well as trans-drug delivery), oral mucosal, dermal, ungual and intravaginal systems.

Expert opinion: Interest in HME as a pharmaceutical process continues to grow and the potential of automation and reduction of capital investment and labor costs has earned this technique a necessary consideration as a drug delivery solution.     

A Solid-State Approach to Enable Early Development Compounds: Selection and Animsal Bioavailability Studies of an Itraconazole Amorphous Solid Dispersion

A solid-state approach to enable compounds in preclinical development is used by identifying an amorphous solid dispersion in a simple formulation to increase bioavailability. Itraconazole (ITZ) was chosen as a model crystalline compound displaying poor aqueous solubility and low bioavailability. Solid dispersions were prepared with different polymers (PVP K-12, K29/32, K90; PVP VA S-630; HPMC-P 55; and HPMC-AS HG) at varied concentrations (1:5, 1:2, 2:1, 5:1 by weight) using two preparation methods (evaporation and freeze drying). Physical characterization and stability data were collected to examine recommended storage, handling, and manufacturing conditions. Based on generated data, a 1:2 (w/w) ITZ/HPMC-P dispersion was selected for further characterization, testing, and scale-up. Thermal data and computational analysis suggest that it is a possible solid nanosuspension. The dispersion was successfully scaled using spray drying, with the materials exhibiting similar physical properties as the screening samples. A simple formulation of 1:2 (w/w) ITZ/HPMC-P dispersion in a capsule was compared to crystalline ITZ in a capsule in a dog bioavailability study, with the dispersion being significantly more bioavailable. This study demonstrated the utility of using an amorphous solid form with desirable physical properties to significantly improve bioavailability and provides a viable strategy for evaluating early drug candidates. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3901–3922, 2010     

Recent developments in drug-eluting dressings for the treatment of chronic wounds

Introduction: Granulation is a key unit process in the production of pharmaceutical solid dosage forms and involves the agglomeration of fine particles with the aid of a binding agent. Fluidized bed granulation, a classic example of spray granulation, is a technique of particle agglomeration brought about by the spray addition of the binding liquid onto a stationary bed of powder particles that is transformed to a fluid-like state by the passage of air through it.

Areas covered: The basic working principles, equipment set-up, advantages and challenges of fluidized bed granulation are introduced in this review. This is followed by an overview of the formulation and process-related variables affecting granulation performance. Technological advances, particularly in the application of process analytical tools, in the field of fluidized bed granulation research are also discussed.

Expert opinion: Fluidized bed granulation is a popular technique for pharmaceutical production, as it is a highly economical and efficient one-pot process. The research and development of process analytical technologies (PAT) has allowed greater process understanding and control to be achieved, even for the lesser known fluidized bed techniques, such as bottom spray and fluidized hot melt granulation. In view of its consistent mixing, as well as continuous and concurrent wetting and drying occurring throughout processing, fluidized bed granulation shows great potential for continuous production although more research is required to fully implement, validate and integrate the PAT tools in a production line.     

Solid dispersions,Part II: new strategies in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs

Introduction: The absorption of poorly water-soluble drugs, when presented in the crystalline state to the gastrointestinal tract, is typically dissolution rate-limited, and according to BCS these drugs belong mainly to class II. Both dissolution kinetics and solubility are particle size dependent. Nowadays, various techniques are available to the pharmaceutical industry for dissolution rate enhancement of such drugs. Among such techniques, nanosuspensions and drug formulation in solid dispersions are those with the highest interest.

Areas covered: This review discusses strategies undertaken over the last 10 years, which have been applied for the dissolution enhancement of poorly water-soluble drugs; such processes include melt mixing, electrospinning, microwave irradiation and the use of inorganic nanoparticles.

Expert opinion: Many problems in this field still need to be solved, mainly the use of toxic solvents, and for this reason the use of innovative new procedures and materials will increase over the coming years. Melt mixing remains extremely promising for the preparation of SDs and will probably become the most used method in the future for the preparation of solid drug dispersions.     

Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: Formulation and process considerations

Spray drying is an efficient technology for solid dispersion manufacturing since it allows extreme rapid solvent evaporation leading to fast transformation of an API-carrier solution to solid API-carrier particles. Solvent evaporation kinetics certainly contribute to formation of amorphous solid dispersions, but also other factors like the interplay between the API, carrier and solvent, the solution state of the API, formulation parameters (e.g. feed concentration or solvent type) and process parameters (e.g. drying gas flow rate or solution spray rate) will influence the final physical structure of the obtained solid dispersion particles. This review presents an overview of the interplay between manufacturing process, formulation parameters, physical structure, and performance of the solid dispersions with respect to stability and drug release characteristics.     

Formation and characterization of solid dispersions of piroxicam and polyvinylpyrrolidone using spray drying and precipitation with compressed antisolvent

Solid dispersions of a poorly water-soluble drug piroxicam in polyvinylpyrrolidone (PVP) were prepared by precipitation with compressed antisolvent (PCA) and spray drying techniques. Physicochemical properties of the products and drug-polymer interactions were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry, etc. Piroxicam was found amorphously dispersed in both solid dispersion systems with the drug to polymer weight ratio of 1:4. Spectra data indicated the formation of hydrogen bonding between the drug and the polymer. Both techniques evaluated in this work resulted in improved dissolution of piroxicam. By comparison, PCA-processed solid dispersions showed distinctly superior performance in that piroxicam dissolved completely within the first 5 min and the dissolution rate was at least 20 times faster than raw drug did within the first 15 min. PCA processing could provide an effective pharmaceutical formulation technology to improve the bioavailability of poorly water-soluble drug.     

Effects of Surfactants on Itraconazole-Hydroxypropyl Methylcellulose Acetate Succinate Solid Dispersion Prepared by Hot Melt Extrusion. II: Rheological Analysis and Extrudability Testing

Although hydroxypropyl methylcellulose acetate succinate (HPMCAS) has been widely used as a carrier for amorphous solid dispersion of poorly water-soluble drugs, its application has mostly been limited to spray drying, and the solvent-free method of hot melt extrusion has rarely been used. This is on account of the high temperature (≥170°C) required for extrusion where the polymer and even a drug may degrade. In part 1 of this series of papers, we demonstrated that HPMCAS is miscible with surfactants such as, poloxamer 188, poloxamer 407 and d-alpha tocopheryl polyethylene glycol 1000 succinate, which may also serve as plasticizers (Solanki et al., J Pharm Sci. 2019; 108 (4):1453-1465). The present investigation was undertaken to determine plasticization effects of the surfactants and a model drug, itraconazole, in reducing melt extrusion temperatures of HPMCAS. The determination of complex viscosity as functions of temperature and also as functions of angular frequency at certain fixed temperatures showed that the surfactants and the drug greatly reduce viscosity of HPMCAS by their plasticization effects. Surfactants and drug also had synergistic effects in reducing viscosity. The torque analysis during melt extrusion demonstrated that these additives greatly enhanced extrudability of HPMCAS. Surfactant-drug-polymer mixtures were successfully extruded as stable amorphous solid dispersions at 130°C, which is much lower than the minimum extrusion temperature of 170°C for neat HPMCAS.     

大黄素固体分散体制备、表征与释药机制研究

摘要：目的 制备大黄素固体分散体，提高其体外溶出度并探究其释药机制。方法 采用分子对接技术，辅助筛选聚合物载体。以大黄素为原料药，Kollidon VA64为聚合物载体，采用热熔挤出工艺制备大黄素固体分散体。通过溶出仪测定其体外溶出，利用SEM，DCS和PXRD对原料药和固体分散体的表面形态和晶型进行表征，最后采用FTIR，NMR和分子动力学模拟对固体分散体的释药机制进行探究。结果 相较于大黄素原料药，大黄素固体分散体在4种介质中的溶出被明显改善，大黄素由结晶态转化为无定形态，药物与聚合物载体间形成了氢键。结论 固体分散体中药物晶型的转变和氢键的产生是改善药物体外溶出的主要因素。