Development of Itraconazole Tablets Containing Viscous KinetiSol Solid Dispersions: In Vitro and In Vivo Analysis in Dogs.

The formulation factors relevant to developing immediate and controlled release dosage forms containing poorly soluble drugs dispersed in amorphous systems are poorly understood. While the utility of amorphous solid dispersions is becoming apparent in the pharmaceutical marketplace, literature reports tend to concentrate on the development of solid dispersion particulates, which then must be formulated into a tablet. Amorphous solid dispersions of itraconazole in high molecular weight hydroxypropyl methylcellulose were prepared by KinetiSol® Dispersing and tablets were formulated to immediately disintegrate or control the release of itraconazole. Formulated tablets were evaluated by two non-sink dissolution methodologies and the dosage form properties that controlled the gelling tendency of the dispersion carrier, hydroxypropyl methylcellulose, were investigated. Selected formulations were evaluated in an exploratory beagle dog pharmacokinetic study; the results of which indicate potential for a prolonged absorption phase relative to the commercially extruded control.

Hot melt extrusion versus spray drying: hot melt extrusion degrades albendazole.

The purpose of this study was to enhance the dissolution properties of albendazole (ABZ) by the use of amorphous solid dispersions. Phase diagrams of ABZ-polymer binary mixtures generated from Flory-Huggins theory were used to assess miscibility and processability. Forced degradation studies showed that ABZ degraded upon exposure to hydrogen peroxide and 1 N NaOH at 80 °C for 5 min, and the degradants were albendazole sulfoxide (ABZSX), and ABZ impurity A, respectively. ABZ was chemically stable following exposure to 1 N HCl at 80 °C for one hour. Thermal degradation profiles show that ABZ, with and without Kollidon® VA 64, degraded at 180 °C and 140 °C, respectively, which indicated that ABZ could likely be processed by thermal processing. Following hot melt extrusion, ABZ degraded up to 97.4%, while the amorphous ABZ solid dispersion was successfully prepared by spray drying. Spray-dried ABZ formulations using various types of acids (methanesulfonic acid, sulfuric acid and hydrochloric acid) and polymers (Kollidon® VA 64, Soluplus® and Eudragit® E PO) were studied. The spray-dried ABZ with methanesulfonic acid and Kollidon® VA 64 substantially improved non-sink dissolution in acidic media as compared to bulk ABZ (8-fold), physical mixture of ABZ:Kollidon® VA 64 (5.6-fold) and ABZ mesylate salt (1.6-fold). No degradation was observed in the spray-dried product for up to six months and less than 5% after one-year storage. In conclusion, amorphous ABZ solid dispersions in combination with an acid and polymer can be prepared by spray drying to enhance dissolution and shelf-stability, whereas those made by melt extrusion are degraded.

Influence of process parameters on the preparation of pharmaceutical films by electrostatic powder deposition.

Electrostatic powder deposition (ESPD) has been developed as a solvent-free method to prepare pharmaceutical films. The aim of this work was to investigate the influence of process parameters during (1) electrostatic powder deposition, (2) curing, and (3) removal of the film from the substrate on the properties of the film. Polyethylene oxide (PEO) was used as the model polymer and stainless steel 316 as the substrate. Deposition efficiency (i.e. deposited weight) was measured with varying charging voltage, gun tip to substrate distance, and environmental humidity. Scanning electron microscopy was utilized to assess film formation, and adhesive and mechanical strength of films were measured with varying cure temperature and time. Adhesive strength was measured for films prepared on substrates of varying surface roughness. When deposition was performed at low humidity conditions, 25%RH, process parameters did not significantly affect deposition behavior. At 40%RH, increasing deposition efficiency with decreasing gun tip to substrate distance and increasing voltage (up to 60kV) was observed. Complete film formation was seen by 30min at 80°C, compared to lower curing temperatures and times. All films were readily removed from the substrates. The results show the ESPD process can be modified to produce films with good mechanical properties (e.g. tensile strength>0.06MPa), suggesting it is a promising dry powder process for preparing pharmaceutical films.

A New Extrudable Form of Hypromellose: AFFINISOL™ HPMC HME.

Hypromellose is a hydrophilic polymer widely used in immediate- and modified-release oral pharmaceutical dosage forms. However, currently available grades of hypromellose are difficult, if not impossible, to process by hot melt extrusion (HME) because of their high glass transition temperature, high melt viscosity, and low degradation temperature. To overcome these challenges, a modified grade of hypromellose, AFFINISOL™ HPMC HME, was recently introduced. It has a significantly lower glass transition temperature and melt viscosity as compared to other available grades of hypromellose. The objective of this paper is to assess the extrudability and performance of AFFINISOL™ HPMC HME (100LV and 4M) as compared to other widely used polymers in HME, including HPMC 2910 100cP (the currently available hypromellose), Soluplus®, Kollidon® VA 64, and EUDRAGIT® E PO. Formulations containing polymer and carbamazepine (CBZ) were extruded on a co-rotating 16-mm twin-screw extruder, and the effect of temperature, screw speed, and feed rate was investigated. The performance of the solid dispersions was evaluated based on Flory-Huggins modeling and characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), Raman spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, and dissolution. All formulations extruded well except for HPMC 2910 100cP, which resulted in over-torqueing the extruder (machine overloading because the motor cannot provide efficient energy to rotate the shaft). Among the HME extrudates, only the EUDRAGIT® E PO formulation was crystalline as confirmed by DSC, XRD, and Raman, which agreed with predictions from Flory-Huggins modeling. Dissolution testing was conducted under both sink and non-sink conditions. Sink dissolution testing in neutral media revealed that amorphous CBZ in the HME extrudates completely dissolved within 15 min, which was much more rapid than the time for complete dissolution of bulk CBZ (60 min) and EUDRAGIT® E PO solid dispersion (more than 6 h). Non-sink dissolution in acidic media testing revealed that only CBZ contained in the AFFINISOL™ HPMC HME, and EUDRAGIT® E PO solid dispersions rapidly supersaturated after 15 min, reaching a twofold drug concentration compared to the CBZ equilibrium solubility. In summary, AFFINISOL™ HPMC HME 100LV and AFFINISOL™ HPMC HME 4M are useful in the pharmaceutical HME process to increase wetting and dissolution properties of poorly water-soluble drugs like CBZ.

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1).

Polyvinyl alcohol (PVAL) has not been investigated in a binary formulation as a concentration-enhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol® dispersing (KSD) technology, PVAL has been enabled for this application and it is the aim of this paper to investigate various grades for improvement of the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients. Solid amorphous dispersions were created with the model drug, itraconazole (ITZ), at a selected drug loading of 20%. Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, size exclusion chromatography, and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. The 4-88 grade of PVAL was determined to be effective at enhancing solubility and bioavailability of itraconazole.

Bioavailability enhancement of a BCS IV compound via an amorphous combination product containing ritonavir.

OBJECTIVES: To evaluate the effect of ritonavir (RTV) co-administration on the bioavailability of an amorphous dispersion of acetyl-11-keto-beta-boswellic acid (AKBA) and to develop a pharmaceutically acceptable AKBA-RTV combination tablet. METHODS: A pharmacokinetic (PK) study in rats was conducted to evaluate the influence of RTV co-administration on the oral bioavailability of an AKBA amorphous dispersion. KinetiSol was utilized to enable production of an improved RTV formulation that facilitated the development of an AKBA-RTV combination tablet. Following in-vitro characterization, the PK performance of the tablets was evaluated in male beagles. KEY FINDINGS: Co-administration of RTV increased oral absorption of AKBA by about fourfold over the AKBA dispersion alone and approximately 24-fold over the pure compound. The improved RTV amorphous dispersion exhibited similar purity and neutral-phase dissolution to Norvir. The AKBA-RTV combination tablets yielded a substantial increase in AKBA's bioavailability in dogs. CONCLUSIONS: Oral absorption of AKBA is substantially limited by intestinal CYP3A activity and poor aqueous solubility. Consequently, AKBA's oral bioavailability is maximized by administration from a supersaturating formulation in conjunction with a CYP3A inhibitor. The AKBA-RTV combination tablet presented herein represents a breakthrough in the oral delivery of the compound facilitating future use as a drug therapy for broad spectrum cancer treatment.

Continuous twin screw melt granulation of glyceryl behenate: Development of controlled release tramadol hydrochloride tablets for improved safety.

Interest in granulation processes using twin screw extrusion machines is rapidly growing. The primary objectives of this study were to develop a continuous granulation process for direct production of granules using this technique with glyceryl behenate as a binder, evaluate the properties of the resulting granules and develop controlled release tablets containing tramadol HCl. In addition, the granulation mechanism was probed and the polymorphic form of the lipid and drug release rate were evaluated on stability. Granules were prepared using a Leistritz NANO16 twin screw extruder operated without a constricting die. The solid state of the granules were characterized by differential scanning calorimetry and X-ray diffraction. Formulated tablets were studied in 0.1N HCl containing 0-40% ethanol to investigate propensity for alcohol induced dose dumping. The extrusion barrel temperature profile and feed rate were determined to be the primary factors influencing the particle size distribution. Granules were formed by a combination immersion/distribution mechanism, did not require subsequent milling, and were observed to contain desirable polymorphic forms of glyceryl behenate. Drug release from tablets was complete and controlled over 16 h and the tablets were determined to be resistant to alcohol induced dose dumping. The drug release rate from the tablets was found to be stable at 40°C and 75% relative humidity for the duration of a 3 month study.

Investigation of the interactions of enteric and hydrophilic polymers to enhance dissolution of griseofulvin following hot melt extrusion processing.

OBJECTIVES: This study focuses on the application of hot melt extrusion (HME) to produce solid dispersions containing griseofulvin (GF) and investigates the in-vitro dissolution performance of HME powders and resulting tablet compositions containing HME-processed dispersions. METHODS: Binary, ternary and quaternary dispersions containing GF, enteric polymer (Eudragit L100-55 or AQOAT-LF) and/or vinyl pyrrolidone-based polymer (Plasdone K-12 povidone or S-630 copovidone) were processed by HME. Two plasticizers, triethyl citrate (TEC) and acetyl tributyl citrate (ATBC), were incorporated to aid in melt processing and to modify release of GF in neutral media following a pH-change in dissolution. Products were characterized for GF recovery, degrees of compositional amorphous character, intermolecular interactions and non-sink dissolution performance. KEY FINDINGS: Binary dispersions exhibited lower maximum observed concentration values and magnitudes of supersaturated GF in neutral media dissolution in comparison with the ternary dispersions. The quaternary HME products, 1 : 2 : 1 : 0.6 GF : L100-55 : S-630 : ATBC and GF : AQOAT-LF : K-12 : ATBC, were determined as the most optimal concentration-enhancing compositions due to increased hydrogen bonding of enteric functional groups with carbonyl/acetate groups of vinyl pyrrolidone-based polymers, reduced compositional crystallinity and presence of incorporated hydrophobic plasticizer. CONCLUSIONS: HME products containing combinations of concentration-enhancing polymers can supersaturate and sustain GF dissolution to greater magnitudes in neutral media following the pH-transition and be compressed into immediate-release tablets exhibiting similar dissolution profiles.

The incorporation of low-substituted hydroxypropyl cellulose into solid dispersion systems.

While the use of amorphous solid dispersions to improve aqueous solubility is well documented, little consideration has traditionally been given to the finished dosage form. The objective of this study was to evaluate the dissolution performance of amorphous solid dispersions containing a dispersed superdisintegrant with binding properties. KinetiSol® dispersing was used to thermally process hypromellose acetate succinate-based compositions containing the drug substance nifedipine (NIF) and a highly compressible grade of low-substituted hydroxypropyl cellulose (New Binder Disintegrants; NBD-grade). Solid-state analysis demonstrated that compositions were rendered amorphous during processing. Tablets containing intra-dispersion NBD were found to exhibit non-sink dissolution performance similar to milled intermediate, demonstrating excellent disintegration characteristics. Conversely, tablets without intra-dispersion NBD were found to release significantly less NIF during dissolution analysis due to particle agglomeration. It was determined that compressibility and particle wetting increased as the level of intra-dispersion NBD increased.

Effect of tablet structure on controlled release from supersaturating solid dispersions containing glyceryl behenate.

The objective of this study was to evaluate the use of glyceryl behenate as a plasticizer and release modifier in solid dispersion systems containing itraconazole and carbamazepine. Amorphous solid dispersions of high molecular weight polyvinylpyrrolidone were prepared by hot-melt extrusion, the processing of which was improved by the inclusion of glyceryl behenate. Dispersions were milled and subsequently compressed into tablets. Solid dispersions were also prepared by KinetiSol Dispersing, which allowed for the manufacture of monolithic tablets of the same composition and shape as compressed tablets. Tablets without glyceryl behenate and all compressed tablets were observed to have an incomplete release profile likely due to drug crystallization within the tablet as this occurred at conditions in which dissolution concentrations were below saturation. Monolithic tablets formulated to be more hydrophobic, by including glyceryl behenate, allowed for sustained release below and above saturation conditions.

Preparation of amorphous solid dispersions by rotary evaporation and KinetiSol Dispersing: approaches to enhance solubility of a poorly water-soluble gum extract.

Acetyl-11-keto-ß-boswellic acid (AKBA), a gum resin extract, possesses poor water-solubility that limits bioavailability and a high melting point making it difficult to successfully process into solid dispersions by fusion methods. The purpose of this study was to investigate solvent and thermal processing techniques for the preparation of amorphous solid dispersions (ASDs) exhibiting enhanced solubility, dissolution rates and bioavailability. Solid dispersions were successfully produced by rotary evaporation (RE) and KinetiSol® Dispersing (KSD). Solid state and chemical characterization revealed that ASD with good potency and purity were produced by both RE and KSD. Results of the RE studies demonstrated that AQOAT®-LF, AQOAT®-MF, Eudragit® L100-55 and Soluplus with the incorporation of dioctyl sulfosuccinate sodium provided substantial solubility enhancement. Non-sink dissolution analysis showed enhanced dissolution properties for KSD-processed solid dispersions in comparison to RE-processed solid dispersions. Variances in release performance were identified when different particle size fractions of KSD samples were analyzed. Selected RE samples varying in particle surface morphologies were placed under storage and exhibited crystalline growth following solid-state stability analysis at 12 months in comparison to stored KSD samples confirming amorphous instability for RE products. In vivo analysis of KSD-processed solid dispersions revealed significantly enhanced AKBA absorption in comparison to the neat, active substance.

Investigation of process temperature and screw speed on properties of a pharmaceutical solid dispersion using corotating and counter-rotating twin-screw extruders.

OBJECTIVE: The use of corotating twin screw hot-melt extruders to prepare amorphous drug/polymer systems has become commonplace. As small molecule drug candidates exiting discovery pipelines trend towards higher MW and become more structurally complicated, the acceptable operating space shifts below the drug melting point. The objective of this research is to investigate the extrusion process space, which should be selected to ensure that the drug is solubilized in the polymer with minimal thermal exposure, is critical in ensuring the performance, stability and purity of the solid dispersion. METHODS: The properties of a model solid dispersion were investigated using both corotating and counter-rotating hot-melt twin-screw extruders operated at various temperatures and screw speeds. The solid state and dissolution performance of the resulting solid dispersions was investigated and evaluated in context of thermodynamic predictions from Flory-Huggins Theory. In addition, the residence time distributions were measured using a tracer, modelled and characterized. KEY FINDINGS: The amorphous content in the resulting solid dispersions was dependent on the combination of screw speed, temperature and operating mode. CONCLUSIONS: The counter-rotating extruder was observed to form amorphous solid dispersions at a slightly lower temperature and with a narrower residence time distribution, which also exhibited a more desirable shape.

Enhancing bioavailability through thermal processing.

Formulation intervention, through the application of processing technologies, is a requirement for enabling therapy for the vast majority of drugs. Without these enabling technologies, poorly soluble drugs may not achieve therapeutic concentrations in the blood or tissue of interest. Conversely, freely soluble and/or rapidly cleared drugs may require frequent dosing resulting in highly cyclic tissue concentrations. During the last several years, thermal processing techniques, such as melt mixing, spray congealing, sintering, and hot-melt extrusion, have evolved rapidly and several new technologies, specifically dry powder coating, injection molding, and KinetiSol(®) dispersing, have been adapted to the pharmaceutical arena. An examination of the contemporary literature is reported in this review to summarize the variety and utility of thermal processing technologies employed for solubility enhancement and controlled release. In particular, the impact of these processing technologies on bioavailability, considered in terms of both rate and extent, has been reviewed.

The use of inorganic salts to improve the dissolution characteristics of tablets containing Soluplus®-based solid dispersions.

The dissolution enhancement advantages inherent to amorphous solid dispersions systems are often not fully realized once they are formulated into a solid dosage form. The objective of this study was to investigate the ability of inorganic salts to improve the dissolution rate of carbamazepine (CBZ) from tablets containing a high loading of a Soluplus®-based solid dispersion. Cloud point and viscometric studies were conducted on Soluplus® solutions to understand the effect of temperature, salt type and salt concentration on the aqueous solubility and gelling tendencies of Soluplus®, properties that can significantly impact dissolution performance. Studies indicated that Soluplus® exhibited a cloud point that was strongly dependent on the salt type and salt concentration present in the dissolving medium. The presence of kosmotropic salts dehydrated the polymer, effectively lowering the cloud point and facilitating formation of a thermoreversible hydrogel. The ability of ions to impact the cloud point and gel strength generally followed the rank order of the Hofmeister series. Solid dispersions of CBZ and Soluplus® were prepared by KinetiSol® Dispersing, characterized to confirm an amorphous composition was formed and incorporated into tablets at very high levels (70% w/w). Dissolution studies demonstrated the utility of including salts in tablets to improve dissolution properties. Tablets that did not contain a salt or those that included a chaotropic salt hydrated at the tablet surface and did not allow for sufficient moisture ingress into the tablet. Conversely, the inclusion of kosmotropic salts allowed for rapid hydration of the entire tablet and the formation of a gel structure with strength dependent on the type of salt utilized. Studies also showed that, in addition to allowing tablet hydration, potassium bicarbonate and potassium carbonate provided effervescence which effectively destroyed the gel network and allowed for rapid dissolution of CBZ. Subsequent dissolution studies in 0.1 N HCl showed that potassium bicarbonate was an effective tablet disintegrant at levels as low as 1% and provided for tablets that rapidly disintegrated over a wide range of applied compression forces, presumably due to synergy between the ability to form a weak hydrogel structure and carbon dioxide liberation. Similar dissolution performance was measured in pH 4.5 acetate buffer, despite reduced polymer solubility caused by kosmotropic salts in solution, demonstrating robustness. With the use of inorganic salts such as potassium bicarbonate, it may be possible to substantially improve disintegration and dissolution characteristics of tablets containing Soluplus®.

Preparation and characterization of fusion processed solid dispersions containing a viscous thermally labile polymeric carrier.

The primary aim of the present study was to investigate the ability of hydroxypropyl and methoxyl substituted cellulose ethers to stabilize supersaturated concentrations of itraconazole (ITZ), a poorly water-soluble weak base, after an acid-to-neutral pH transition. A secondary aim of the study was to evaluate the effect of fusion processes on polymer stability and molecular weight. Polymer screening studies showed that stabilization of ITZ supersaturation was related to the molecular weight of the polymer and levels of hydroxypropyl and methoxyl substitution. METHOCEL E50LV (E50LV), which is characterized as having a high melt viscosity, was selected for solid dispersion formulation studies. Hot-melt extrusion processing of E50LV based compositions resulted in high torque loads, low material throughput and polymer degradation. KinetiSol Dispersing, a novel fusion based processing technique, was evaluated as a method to prepare the solid dispersions with reduced levels of polymer degradation. An experimental design revealed that polymer molecular weight was sensitive to shearing forces and high temperatures. However, optimal processing conditions resulted in significantly reduced E50LV degradation relative to HME processing. The technique was effectively utilized to prepare homogenous solid solutions of E50LV and ITZ, characterized as having a single glass transition temperature over a wide range of drug loadings. All prepared compositions provided for a high degree of ITZ supersaturation stabilization.

Thermal processing of a poorly water-soluble drug substance exhibiting a high melting point: the utility of KinetiSol® Dispersing.

Poorly water-soluble drug substances that exhibit high melting points are often difficult to successfully process by fusion-based techniques. The purpose of this study was to identify a suitable polymer system for meloxicam (MLX), a high melting point class II BCS compound, and investigate thermal processing techniques for the preparation of chemically stable single phase solid dispersions. Thermal and solution based screening techniques were utilized to screen hydrophilic polymers suitable for immediate release formulations. Results of the screening studies demonstrated that Soluplus(®)(SOL) provided the highest degree of miscibility and solubility enhancement. A hot-melt extrusion feasibility study demonstrated that high temperatures and extended residence times were required in order to render compositions amorphous, causing significant degradation of MLX. A design of experiments (DOE) was conducted on the KinetiSol(®) Dispersing (KSD) process to evaluate the effect of processing conditions on the chemical stability and amorphous character of MLX. The study demonstrated that ejection temperature significantly impacted MLX stability. All samples prepared by KSD were substantially amorphous. Dissolution analysis of the KSD processed solid dispersions showed increased dissolution rates and extent of supersaturation over the marketed generic MLX tablets.