Production Of Solid Dispersions Research Articles

Improved Vemurafenib Dissolution and Pharmacokinetics as an Amorphous Solid Dispersion Produced by KinetiSol® Processing.

Vemurafenib is a poorly soluble, low permeability drug that has a demonstrated need for a solubility-enhanced formulation. However, conventional approaches for amorphous solid dispersion production are challenging due to the physiochemical properties of the compound. A suitable and novel method for creating an amorphous solid dispersion, known as solvent-controlled coprecipitation, was developed to make a material known as microprecipitated bulk powder (MBP). However, this approach has limitations in its processing and formulation space. In this study, it was hypothesized that vemurafenib can be processed by KinetiSol into the same amorphous formulation as MBP. The KinetiSol process utilizes high shear to rapidly process amorphous solid dispersions containing vemurafenib. Analysis of the material demonstrated that KinetiSol produced amorphous, single-phase material with acceptable chemical purity and stability. Values obtained were congruent to analysis conducted on the comparator material. However, the materials differed in particle morphology as the KinetiSol material was dense, smooth, and uniform while the MBP comparator was porous in structure and exhibited high surface area. The particles produced by KinetiSol had improved in-vitro dissolution and pharmacokinetic performance for vemurafenib compared to MBP due to slower drug nucleation and recrystallization which resulted in superior supersaturation maintenance during drug release. In the in-vivo rat pharmacokinetic study, both amorphous solid dispersions produced by KinetiSol exhibited mean AUC values at least two-fold that of MBP when dosed as a suspension. It was concluded that the KinetiSol process produced superior dosage forms containing vemurafenib with the potential for substantial reduction in patient pill burden.

Extraction Optimization and Structural and Thermal Characterization of the Antimicrobial Abietane 7α-Acetoxy-6β-hydroxyroyleanone.

The abietane 7α-acetoxy-6β-hydroxyroyleanone (AHR), obtained from plant extracts, is an attractive lead for drug development, given its known antimicrobial properties. Two basic requirements to establish any compound as a new drug are the development of a convenient extraction process and the characterization of its structural and thermal properties. In this work seven different methods were tested to optimize the extraction of AHR from Plectranthus grandidentatus. Supercritical fluid extraction (SFE) proved to be the method of choice, delivering an amount of AHR (57.351 μg·mg-1) approximately six times higher than the second best method (maceration in acetone; 9.77 μg·mg-1). Single crystal X-ray diffraction analysis of the ARH molecular and crystal structure carried out at 167 ± 2 K and 296 ± 2 K showed only a single phase, here dubbed form III (orthorhombic space group P21212), at those temperatures. The presence of two other polymorphs above room temperature was, however, evidenced by differential scanning calorimetry (DSC). The three forms are enantiotropically related, with the form III → form II and form II → form I transitions occurring at 333.5 ± 1.6 K and 352.0 ± 1.6 K, respectively. The fact that the transitions are reversible suggests that polymorphism is not likely to be an issue in the development pharmaceutical formulations based on ARH. DSC experiments also showed that the compound decomposes on melting at 500.8 ± 0.8 K. Melting should therefore be avoided if, for example, strategies to improve solubility based on the production of glassy materials or solid dispersions are considered.

New Strategies for Improving the Development and Performance of Amorphous Solid Dispersions.

The understanding of amorphous solid dispersions has grown significantly in the past decade. This is evident from the number of approved commercial amorphous solid dispersion products. While amorphous formulation is considered an enabling technology, it has become the norm for formulating poorly soluble compounds. Despite this success, improvements can still be made that enable early development formulation decisions, to develop a rationale for selecting a manufacturing process, to overcome degradation and phase separation during processing, to help achieve physical stability during storage, and to optimize dissolution behavior. The purpose of this literature review is to present recently reported strategies for improving the development and performance of ASDs. The benefits and limitations of each strategy as well as recent relevant case studies will be presented in this review. The strategies are presented from three different aspects: (a) prediction techniques that enable formulation decisions, (b) manufacturing considerations that help produce physically and chemically stable ASDs, and

Inline UV/Vis spectroscopy as PAT tool for hot-melt extrusion.

Hot-melt extrusion on co-rotating twin screw extruders is a focused technology for the production of pharmaceuticals in the context of Quality by Design. Since it is a continuous process, the potential for minimizing product quality fluctuation is enhanced. A typical application of hot-melt extrusion is the production of solid dispersions, where an active pharmaceutical ingredient (API) is distributed within a polymer matrix carrier. For this dosage form, the product quality is related amongst others to the drug content. This can be monitored on- or inline as critical quality attribute by a process analytical technology (PAT) in order to meet the specific requirements of Quality by Design. In this study, an inline UV/Vis spectrometer from ColVisTec was implemented in an early development twin screw extruder and the performance tested in accordance to the ICH Q2 guideline. Therefore, two API (carbamazepine and theophylline) and one polymer matrix (copovidone) were considered with the main focus on the quantification of the drug load. The obtained results revealed the suitability of the implemented PAT tool to quantify the drug load in a typical range for pharmaceutical applications. The effort for data evaluation was minimal due to univariate data analysis, and in combination with a measurement frequency of 1Hz, the system is sufficient for real-time data acquisition.

Efficient production of solid dispersions by spray drying solutions of high solid content using a 3-fluid nozzle

To evaluate the feasibility of producing solid dispersions with 3-fluid nozzle spray drying to improve the dissolution behavior of lipophilic drugs, 60 experiments were performed based on a Design of Experiment. Solid dispersions with mannitol as a hydrophilic matrix and diazepam as a model drug with a drug load of 20 wt-% were produced. The variables of the experiments were the water/organic solvent ratio, liquid feed flow, total solid content, atomizing airflow and type of organic solvent (ethanol or ethyl acetate). The responses measured were dissolution rate, yield, actual drug load, particle size and crystallinity of diazepam and mannitol. Increasing water/organic solvent ratio was found to be the main factor for enhancing the dissolution rate. The total solid content of the solutions to be spray dried did not affect any of the responses, which means that processing solutions of high concentrations is possible. The choice of organic solvent did not affect the responses as well, i.e. both the fully water miscible solvent ethanol and the poorly water miscible solvent ethyl acetate could be used which makes this production method highly versatile.

Formulation and Evaluation of Fast Dissolving Tablets of Taste-Masked Ondansetron Hydrochloride by Solid Dispersion

Ondansetron hydrochloride (ONH) is a very bitter, potent antiemetic drug used for the treatment and/or prophylaxis of chemotherapy or radiotherapy or postoperative induced emesis. The objective of this study is to formulate and evaluate of taste masked fast dissolving tablet (FDTs) of ONH to increase patient compliance. ONH taste masked granules were prepared by solid dispersion technique using Eudragit E100 polymer as an inert carrier. Solvent evaporation and fusion melting methods were used for such preparation. Completely taste masking with zero release of drug in phosphate buffer pH 6.8was obtained from granules prepared by solvent evaporation method using drug: polymer ratio of 1:2, from which four formulas pass pre-compression evaluation and compressed to FDTs and evaluated for their drug content, in-vitro disintegration time, in-vivo disintegration time, wetting time and in vitro drug release profile. F7 which is prepared from solid dispersion product equivalent to the required dose of ONH , Crosspovidone as superdisintegrant, Aspartame as sweetener ,Ross berry as flavor ,Polyvinylpyrolidone K30.3.as binder ,Avicil PH102 and , mannitol as diluents give best in- vitro, in-vivo disintegration time and best drug release profile. Key words: Ondansetron hydrochloride, taste masking, solid dispersion, Eudragit E100.

Formulation and Evaluation of Fast Dissolving Tablets of Taste-Masked Ondansetron Hydrochloride by Solid Dispersion

Ondansetron hydrochloride (ONH) is a very bitter, potent antiemetic drug used for the treatment and/or prophylaxis of chemotherapy or radiotherapy or postoperative induced emesis. The objective of this study is to formulate and evaluate of taste masked fast dissolving tablet (FDTs) of ONH to increase patient compliance.
 ONH taste masked granules were prepared by solid dispersion technique using Eudragit E100 polymer as an inert carrier. Solvent evaporation and fusion melting methods were used for such preparation.
 Completely taste masking with zero release of drug in phosphate buffer pH 6.8was obtained from granules prepared by solvent evaporation method using drug: polymer ratio of 1:2, from which four formulas pass pre-compression evaluation and compressed to FDTs and evaluated for their drug content, in-vitro disintegration time, in-vivo disintegration time, wetting time and in vitro drug release profile.
 F7 which is prepared from solid dispersion product equivalent to the required dose of ONH , Crosspovidone as superdisintegrant, Aspartame as sweetener ,Ross berry as flavor ,Polyvinylpyrolidone K30.3.as binder ,Avicil PH102 and , mannitol as diluents give best in- vitro, in-vivo disintegration time and best drug release profile.
 Key words: Ondansetron hydrochloride, taste masking, solid dispersion, Eudragit E100.

Novel Alternating Current Electrospinning of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) Nanofibers for Dissolution Enhancement: The Importance of Solution Conductivity

Novel, high-yield alternating current electrospinning (ACES) and direct current electrospinning methods were investigated to prepare high-quality hydroxypropylmethylcellulose acetate succinate (HPMCAS) fibers for the dissolution enhancement of poorly soluble spironolactone. Although HPMCAS is of great pharmaceutical importance as a carrier of marketed solid dispersion-based products, it was found to be unprocessable using electrospinning. Addition of small amounts of polyethylene oxide as aid polymer provided smooth fibers with direct current electrospinning but strongly beaded products with ACES. Solution characteristics were thus modified by introducing further excipients. In the presence of sodium dodecyl sulfate, high-quality, HPMCAS-based fibers were obtained even at higher throughput rates of ACES owing to the change in conductivity (rather than surface tension). Replacement of sodium dodecyl sulfate with non-surface-active salts (calcium chloride and ammonium acetate) maintained the fine quality of nanofibers, confirming the importance of conductivity in ACES process. The HPMCAS-based fibers contained spironolactone in an amorphous form according to differential scanning calorimetry and X-ray powder diffraction. In vitro dissolution tests revealed fast drug release rates depending on the salt used to adjust conductivity. The presented results signify that ACES can be a prospective process for high-scale production of fibrous solid dispersions in which conductivity of solution has a fundamental role.

Solid Dispersions for Oral Administration: An Overview of the Methods for their Preparation.

Oral drug delivery remains the most physiological and therefore the most preferred, simplest and easiest administration route. Nevertheless, a multitude of potentially clinically important drugs will not reach the market or achieve their full potential unless their oral bioavailability is improved by formulation. The aim of this review is to present an overview of properties, formulation, excipients and characterization of solid dispersions corresponding to one of the different formulation strategies for design and development of poorly soluble drugs. This work will review and compare in detail the evolution of solid dispersions focused on the different methods of formulation and production of solid dispersions, their stability, their release properties, their pharmacokinetics and methods for their physicochemical characterization.

Continuous production of itraconazole-based solid dispersions by hot melt extrusion: Preformulation, optimization and design space determination

The purpose of this work was to increase the solubility and the dissolution rate of itraconazole, which was chosen as the model drug, by obtaining an amorphous solid dispersion by hot melt extrusion. Therefore, an initial preformulation study was conducted using differential scanning calorimetry, thermogravimetric analysis and Hansen's solubility parameters in order to find polymers which would have the ability to form amorphous solid dispersions with itraconazole. Afterwards, the four polymers namely Kollidon® VA64, Kollidon® 12PF, Affinisol® HPMC and Soluplus®, that met the set criteria were used in hot melt extrusion along with 25wt.% of itraconazole. Differential scanning confirmed that all four polymers were able to amorphize itraconazole. A stability study was then conducted in order to see which polymer would keep itraconazole amorphous as long as possible. Soluplus® was chosen and, the formulation was fine-tuned by adding some excipients (AcDiSol®, sodium bicarbonate and poloxamer) during the hot melt extrusion process in order to increase the release rate of itraconazole. In parallel, the range limits of the hot melt extrusion process parameters were determined. A design of experiment was performed within the previously defined ranges in order to optimize simultaneously the formulation and the process parameters. The optimal formulation was the one containing 2.5wt.% of AcDiSol® produced at 155°C and 100rpm. When tested with a biphasic dissolution test, more than 80% of itraconazole was released in the organic phase after 8h. Moreover, this formulation showed the desired thermoformability value. From these results, the design space around the optimum was determined. It corresponds to the limits within which the process would give the optimized product. It was observed that a temperature between 155 and 170°C allowed a high flexibility on the screw speed, from about 75 to 130rpm.

ChemInform Abstract: Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid‐State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs

AbstractReview: 217 refs.

Conjugation of Hot-Melt Extrusion with High-Pressure Homogenization: a Novel Method of Continuously Preparing Nanocrystal Solid Dispersions.

Over the past few decades, nanocrystal formulations have evolved as promising drug delivery systems owing to their ability to enhance the bioavailability and maintain the stability of poorly water-soluble drugs. However, conventional methods of preparing nanocrystal formulations, such as spray drying and freeze drying, have some drawbacks including high cost, time and energy inefficiency, traces of residual solvent, and difficulties in continuous operation. Therefore, new techniques for the production of nanocrystal formulations are necessary. The main objective of this study was to introduce a new technique for the production of nanocrystal solid dispersions (NCSDs) by combining high-pressure homogenization (HPH) and hot-melt extrusion (HME). Efavirenz (EFZ), a Biopharmaceutics Classification System class II drug, which is used for the treatment of human immunodeficiency virus (HIV) type I, was selected as the model drug for this study. A nanosuspension (NS) was first prepared by HPH using sodium lauryl sulfate (SLS) and Kollidon® 30 as a stabilizer system. The NS was then mixed with Soluplus® in the extruder barrel, and the water was removed by evaporation. The decreased particle size and crystalline state of EFZ were confirmed by scanning electron microscopy, zeta particle size analysis, and differential scanning calorimetry. The increased dissolution rate was also determined. EFZ NCSD was found to be highly stable after storage for 6months. In summary, the conjugation of HPH with HME technology was demonstrated to be a promising novel method for the production of NCSDs.

Application of spherical silicate to prepare solid dispersion dosage forms with aqueous polymers

The objective of this study is to prepare and characterize solid dispersions of nifedipine (NP) using porous spherical silicate micro beads (MB) that were approximately 100μm in diameter with vinylpyrrolidone/vinyl acetate copolymer (PVP/VA) and a Wurster-type fluidized bed granulator. Compared with previously reported solid dispersion using only MB, the supersaturation of NP dissolved from the proposed system of MB and PVP/VA was maintained during dissolution tests. The proposed system produced a solid dispersion product coated on MB, and morphology was maintained after the coating process to prepare solid dispersion; therefore, the powder characteristics, such as flowability of the proposed solid dispersion product, was tremendously preferable to that of the conventional spray-dried solid dispersions of NP with PVP/VA, expecting to make the consequent manufacturing processes easy for development. Another advantage in the terms of manufacturing is its simple process to prepare solid dispersion by spraying the drug and polymer that were dissolved in an organic solvent onto a MB in a Wurster-type fluidized bed granulator, thus, simplifying the optimization and scale-up with ease.

High speed electrospinning for scaled-up production of amorphous solid dispersion of itraconazole

High speed electrospinning (HSES), compatible with pharmaceutical industry, was used to demonstrate the viability of the preparation of drug-loaded polymer nanofibers with radically higher productivity than the known single-needle electrospinning (SNES) setup. Poorly water-soluble itraconazole (ITRA) was formulated with PVPVA64 matrix polymer using four different solvent-based methods such as HSES, SNES, spray drying (SD) and film casting (FC). The formulations were assessed in terms of improvement in the dissolution rate of ITRA (using a “tapped basket” dissolution configuration) and analysed by SEM, DSC and XRPD. Despite the significantly increased productivity of HSES, the obtained morphology was very similar to the SNES nanofibrous material. ITRA transformed into an amorphous form, according to the DSC and XRPD results, in most cases except the FC samples. The limited dissolution of crystalline ITRA could be highly improved: fast dissolution occurred (>90% within 10min) in the cases of both (the scaled-up and the single-needle) types of electrospun fibers, while the improvement in the dissolution rate of the spray-dried microspheres was significantly lower. Production of amorphous solid dispersions (ASDs) with the HSES system proved to be flexibly scalable and easy to integrate into a continuous pharmaceutical manufacturing line, which opens new routes for the development of industrially relevant nanopharmaceuticals.

Thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding

This study evaluated thermoplastic polyurethanes (TPUR) as matrix excipients for the production of oral solid dosage forms via hot melt extrusion (HME) in combination with injection molding (IM). We demonstrated that TPURs enable the production of solid dispersions – crystalline API in a crystalline carrier – at an extrusion temperature below the drug melting temperature (Tm) with a drug content up to 65% (wt.%). The release of metoprolol tartrate was controlled over 24h, whereas a complete release of diprophylline was only possible in combination with a drug release modifier: polyethylene glycol 4000 (PEG 4000) or Tween 80. No burst release nor a change in tablet size and geometry was detected for any of the formulations after dissolution testing. The total matrix porosity increased gradually upon drug release. Oral administration of TPUR did not affect the GI ecosystem (pH, bacterial count, short chain fatty acids), monitored via the Simulator of the Human Intestinal Microbial Ecosystem (SHIME). The high drug load (65wt.%) in combination with (in vitro and in vivo) controlled release capacity of the formulations, is noteworthy in the field of formulations produced via HME/IM.

Determination of tacrolimus crystalline fraction in the commercial immediate release amorphous solid dispersion products by a standardized X-ray powder diffraction method with chemometrics

Clinical performance of an amorphous solid dispersion (ASD) drug product is related to the amorphous drug content because of the greater bioavailability of this form of the drug than its crystalline form. Therefore, it is paramount to monitor the amorphous and the crystalline fractions in the ASD products. The objective of the present investigation was to study the feasibility of using a standardized X-ray powder diffraction (XRPD) in conjunction with chemometric methods to quantitate the amorphous and crystalline fraction of the drug in several tacrolimus ASD products. Three ASD products were prepared in which drug to excipients ratios ranged from 1:19 to 1:49. The amorphous and crystalline drug products were mixed in various proportions so that amorphous/crystalline tacrolimus in the samples vary from 0 to 100%. XRPD of the samples of the drug products were collected, and PLSR and PCR chemometric methods were applied to the data. The R2 was greater than ‘0.987’ for all the models and bias in the models were statistically insignificant (p>0.05). RMSEP and SEP values were smaller for PLSR models than PCR models. The models prediction capabilities were good and can predict as low as 10% when drug to excipient ratio is as high as 1:49. In summary, XRPD and chemometric provide powerful analytical tools to monitor the crystalline fractions of the drug in the ASD products.

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.

Hot-melt Extrusion Technology and Pharmaceutical Application

The use of hot-melt extrusion (HME) within the pharmaceutical industry is steadily increasing, due to its proven ability to efficiently manufacture novel products. The process has been utilized readily in the plastics industry for over a century and has been used to manufacture medical devices for several decades. The development of novel drugs with poor solubility and bioavailability brought the application of HME into the realm of drug-delivery systems. This has specifically been shown in the development of drug-delivery systems of both solid dosage forms and transdermal patches. HME involves the application of heat, pressure and agitation through an extrusion channel to mix materials together, and subsequently forcing them out through a die. Twin-screw extruders are most popular in solid dosage form development as it imparts both dispersive and distributive mixing. It blends materials while also imparting high shear to break-up particles and disperse them. HME extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier, increasing dissolution rates and bioavailability. The most common difficulty encountered in producing such dispersions is stabilization of amorphous drugs, which prevents them from recrystallization during storage. Pharmaceutical industrial suppliers, of both materials and equipment, have increased their development of equipment and chemicals for specific use with HME. Clearly, HME has been identified as an important and significant process to further enhance drug solubility and solid-dispersion production.

Upscaling of the hot-melt extrusion process: Comparison between laboratory scale and pilot scale production of solid dispersions with miconazole and Kollicoat® IR

Since only limited amount of drug is available in early development stages, the extruder design has evolved towards smaller batch sizes, with a more simple design. An in dept study about the consequences of the differences in design is mandatory and little can be found in literature. Miconazole and Kollicoat® IR were used as model drug and carrier for this study. Two series of solid dispersions were made with a laboratory scale (internal circulation-simple screw design) and a pilot scale extruder (continuous throughput-modular screw design). Efforts were made to match the operating parameters as close as possible (residence time, extrusion temperature and screw speed). The samples were analyzed with modulated DSC straight after production and after exact 24h and 15days storage at −26°C. The kinetic miscibility of the samples prepared with the laboratory scale extruder was slightly higher than the samples prepared with the pilot scale extruder. As the solid dispersions with high drug load were unstable over time, demixing occurred, slightly faster for the samples prepared with the laboratory scale extruder. After 15days, the levels of molecular mixing were comparable, pointing to the predictive value of samples prepared on laboratory scale.

Physical Stabilizing Effect of Biopolymers on Solid Dispersions Containing Indomethacin and Polyethylene Glycol

Solid dispersions of poorly water-soluble drug, indomethacin (IMC), and carriers at a ratio of 1:9 were prepared by melting method. The carriers used in this study were polyethylene glycol 4000 (PEG4000), hydroxypropyl methylcellulose (HPMC) and pectin. The solid dispersions obtained were characterized by powder x-ray diffractometry (PXRD) and dissolution studies. PXRD patterns showed that all solid dispersions led to amorphous products while their physical mixture still showed the crystalline state of drug. Crystalline drug was clearly detectable in solid dispersion products containing only IMC and PEG4000 after storage for 2 months. The formulations with biopolymer (i.e., HPMC, pectin or their combination) showed no drug crystal after storage. More than 80% of IMC dissolved within 5 minutes for all formulations after preparation while less than 40% of IMC dissolved, within 5 minutes, from the formulations containing IMC, PEG4000 and HPMC after storage for 2 months. The slower drug dissolution may be due to the gel-forming properties of HPMC as well as the agglomeration of the products after storage. The results suggested that either HPMC or pectin in solid dispersions can help to prevent the crystallization of amorphous IMC in solid dispersion, probably by a polymer anti-plasticizing effect. Pectin showed superior stabilizing effect with no retardation effect on drug dissolution.