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.

Mucoadhesive amorphous solid dispersions for sustained release of poorly water soluble drugs.

The oral delivery of mucoadhesive patches has been shown to enhance the absorption of large molecules such as peptides. We hypothesized that this mechanism could have utility for poorly soluble small molecules by utilizing a mucoadhesive polymer as the matrix for an amorphous solid dispersion. Binary dispersions of itraconazole and carbomer (Carbopol 71G) were prepared utilizing a thermokinetic mixing process (KinetiSol Dispersing) and the physicochemical properties were investigated by powder X-ray diffraction, calorimetry, and liquid chromatography. Adhesion of the dispersions to freshly excised porcine intestine was investigated with a texture analyzer. Minitablets were compressed from the optimal dispersion and further investigated in vitro and in vivo in rats. Thermokinetic mixing successfully processed amorphous dispersions up to 30% drug loading and each dispersion exhibited works of adhesion that were approximately an order of magnitude greater than a negative control in vitro. Ethylcellulose (EC) coated and uncoated minitablets prepared with the 30% drug load dispersion were delivered orally to rats and exhibited sustained release characteristics, with overall bioavailability greater for the uncoated minitablets compared to the EC-coated minitablets, similar to the rank order observed in our in vitro dissolution experiments. Necropsy studies showed that minitablets delivered with enteric-coated capsules targeted release to the distal small intestine and adhered to the intestinal mucosa, but the rat model presented limitations with respect to evaluating the overall performance. Based on the in vitro and in vivo results, further investigations in larger animals are a logical next step where fluid volumes, pH, and transit times are more favorable for the evaluated dosage forms.

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.

Electrostatic powder coating: Principles and pharmaceutical applications.

A majority of pharmaceutical powders are insulating materials that have a tendency to accumulate charge. This phenomenon has contributed to safety hazards and issues during powder handling and processing. However, increased understanding of this occurrence has led to greater understanding and control of processing and product performance. More recently, the charging of pharmaceutical powders has been employed to adopt electrostatic powder coating as a pharmaceutical process. Electrostatic powder coating is a mature technology used in the finishing industry and much of that knowledge applies to its use in pharmaceutical applications. This review will serve to summarize the principles of electrostatic powder coating and highlight some of the research conducted on its use for the preparation of pharmaceutical dosage forms.

Enabling thermal processing of ritonavir-polyvinyl alcohol amorphous solid dispersions by KinetiSol® Dispersing.

Polyvinyl alcohol has received little attention as a matrix polymer in amorphous solid dispersions (ASDs) due to its thermal and rheological limitations in extrusion processing and limited organic solubility in spray drying applications. Additionally, in extrusion processing, the high temperatures required to process often exclude thermally labile APIs. The purpose of this study was to evaluate the feasibility of processing polyvinyl alcohol amorphous solid dispersions utilizing the model compound ritonavir with KinetiSol® Dispersing (KSD) technology. The effects of KSD rotor speed and ejection temperature on the physicochemical properties of the processed material were evaluated. Powder X-ray diffraction and modulated differential scanning calorimetry were used to confirm amorphous conversion. Liquid chromatography-mass spectroscopy was used to characterize and identify degradation pathways of ritonavir during KSD processing and (13)C nuclear magnetic resonance spectroscopy was used to investigate polymer stability. An optimal range of processing conditions was found that resulted in amorphous product and minimal to no drug and polymer degradation. Drug release of the ASD produced from the optimal processing conditions was evaluated using a non-sink, pH-shift dissolution test. The ability to process amorphous solid dispersions with polyvinyl alcohol as a matrix polymer will enable further investigations of the polymer's performance in amorphous systems for poorly water-soluble compounds.

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions.

Thermal processing technologies continue to gain interest in pharmaceutical manufacturing. However, the types and grades of polymers that can be utilized in common thermal processing technologies, such as hot-melt extrusion (HME), are often limited by thermal or rheological factors. The objectives of the present study were to compare and contrast two thermal processing methods, HME and KinetiSol® Dispersing (KSD), and investigate the influence of polymer type, polymer molecular weight, and drug loading on the ability to produce amorphous solid dispersions (ASDs) containing the model compound griseofulvin (GRIS). Dispersions were analyzed by a variety of imaging, solid-state, thermal, and solution-state techniques. Dispersions were prepared by both HME and KSD using polyvinylpyrrolidone (PVP) K17 or hydroxypropyl methylcellulose (HPMC) E5. Dispersions were only prepared by KSD using higher molecular weight grades of HPMC and PVP, as these could not be extruded under the conditions selected. Powder X-ray diffraction (PXRD) analysis showed that dispersions prepared by HME were amorphous at 10% and 20% drug load; however, it showed significant crystallinity at 40% drug load. PXRD analysis of KSD samples showed all formulations and drug loads to be amorphous with the exception of trace crystallinity seen in PVP K17 and PVP K30 samples at 40% drug load. These results were further supported by other analytical techniques. KSD produced amorphous dispersions at higher drug loads than could be prepared by HME, as well as with higher molecular weight polymers that were not processable by HME, due to its higher rate of shear and torque output.

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.

Challenges and Strategies in Thermal Processing of Amorphous Solid Dispersions: A Review.

Thermal processing of amorphous solid dispersions continues to gain interest in the pharmaceutical industry, as evident by several recently approved commercial products. Still, a number of pharmaceutical polymer carriers exhibit thermal or viscoelastic limitations in thermal processing, especially at smaller scales. Additionally, active pharmaceutical ingredients with high melting points and/or that are thermally labile present their own specific challenges. This review will outline a number of formulation and process-driven strategies to enable thermal processing of challenging compositions. These include the use of traditional plasticizers and surfactants, temporary plasticizers utilizing sub- or supercritical carbon dioxide, designer polymers tailored for hot-melt extrusion processing, and KinetiSol® Dispersing technology. Recent case studies of each strategy will be described along with potential benefits and limitations.

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.

Effect of hydrophilic additives on the dissolution and pharmacokinetic properties of itraconazole-enteric polymer hot-melt extruded amorphous solid dispersions.

Hot-melt extrusion technology has been widely reported for producing amorphous solid dispersions of poorly water-soluble compounds. A number of studies revealed that enteric polymers containing ionizable groups are able to improve the physical stability and maintain drug supersaturation, thereby enhancing oral bioavailability. However, our previous studies found that itraconazole (ITZ)-enteric polymer amorphous solid dispersions are hydrophobic and poorly wettable. Moreover, drug release in an acidic environment (i.e. stomach) is very limited, indicating a narrow absorption window. In the present study, we investigated the effect of hydrophilic additives on the in vitro and in vivo performance of ITZ-enteric polymer amorphous solid dispersions. Incorporating Vitamin E TPGS into ITZ-HPMCAS amorphous solid dispersions significantly improved drug release in the acidic media. Surprisingly, a low concentration of Vitamin E TPGS also enhanced the degree of drug supersaturation in neutral pH media, which is unique as compared with other tested hydrophilic additives. This effect is not due to the solubilization of the surfactant. We further formulated the amorphous solid dispersions into tablet dosage forms and evaluated their performance in a bio-relevant dissolution media. Our optimized formulations exhibited drastically enhanced dissolution profiles as compared with the commercial ITZ product and ITZ amorphous solid dispersion without hydrophilic additive. In vivo study showed that Vitamin E TPGS induced rapid drug absorption after oral administration. Moreover, the elimination half-life of ITZ was prolonged due to the enzyme inhibition effect of Vitamin E TPGS.

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.

Hot-melt extrusion--basic principles and pharmaceutical applications.

Originally adapted from the plastics industry, the use of hot-melt extrusion has gained favor in drug delivery applications both in academia and the pharmaceutical industry. Several commercial products made by hot-melt extrusion have been approved by the FDA, demonstrating its commercial feasibility for pharmaceutical processing. A significant number of research articles have reported on advances made regarding the pharmaceutical applications of the hot-melt extrusion processing; however, only limited articles have been focused on general principles regarding formulation and process development. This review provides an in-depth analysis and discussion of the formulation and processing aspects of hot-melt extrusion. The impact of physicochemical properties of drug substances and excipients on formulation development using a hot-melt extrusion process is discussed from a material science point of view. Hot-melt extrusion process development, scale-up, and the interplay of formulation and process attributes are also discussed. Finally, recent applications of hot-melt extrusion to a variety of dosage forms and drug substances have also been addressed.

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.

Dissolution enhancement of itraconazole by hot-melt extrusion alone and the combination of hot-melt extrusion and rapid freezing--effect of formulation and processing variables.

We investigated the effects of the hot-melt extrusion (HME) process on the properties of itraconazole (ITZ) amorphous solid dispersions made by thin film freezing (TFF) technology. The ITZ-HPMCAS L (1:2) TFF composition exhibited limited drug release in acidic media. HME of the ITZ-HPMCAS TFF composition with hydrophilic carriers improved the drug release rate in acidic media. The type and level of hydrophilic carrier in the composition affected the dissolution profiles of the extrudates. A design of experiments (DoE) study was conducted to elucidate those effects. Hot-melt extrusion processing variables such as extrusion temperature and screw configuration also played a critical role on the properties of the extruded compositions. A higher degree of mixing reduced the crystallinity of semicrystalline excipients and favored the drug release in the acidic media; moreover, the drug precipitation rate in the neutral pH media was reduced.