Proof-of-Concept in Developing a 45% Drug Loaded Amorphous Nanoparticle Formulation.

Amorphous solid dispersion (ASD) is an enabling approach utilized to deliver poorly soluble compounds. ASDs can spontaneously generate drug-rich amorphous nanoparticles upon dissolution, which can act as a reservoir for maintaining supersaturation during oral absorption. But, conventional ASDs are often limited in drug loadings to < 20 %. For indications where the dose is high, this can translate into a significant pill burden. The aim of this research was to develop a high drug loading (DL) amorphous nanoparticle (ANP) formulation that can release the drug-rich nanoparticles into solution upon contact with aqueous environment. Nanoparticles were directly engineered using solvent/anti-solvent precipitation. The obtained nanoparticle suspension was then concentrated followed by solidification to a re-dispersible amorphous dosage form using spray drying or lyophilization. The impact of process variables was studied using dynamic light scattering (DLS), scanning electron microscopy (SEM), high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC). It was observed that spray drying led to a non-re-dispersible formulation. Sucrose and trehalose containing lyocakes resulted in re-dispersible formulations. The trehalose containing lyocakes, in a dog study, gave comparable performance to the reference tablet in the fasted state but lower area under the curve (AUC) in fed state.

Design of Redispersible High-Drug-Load Amorphous Formulations: Impact of Ionic vs Nonionic Surfactants on Processing and Performance.

Amorphous solid dispersions (ASDs) are an enabling formulation approach used to enhance bioavailability of poorly water-soluble molecules in oral drug products. Drug-rich amorphous nanoparticles generated in situ during ASD dissolution maintain supersaturation that drives enhanced absorption. However, in situ formation of nanoparticles requires large quantities of polymers to release drugs rapidly, resulting in an ASD drug load <25%. Delivering directly engineered drug-rich amorphous nanoparticles can reduce the quantities of polymers significantly without sacrificing bioavailability. Preparation of 90% drug-load amorphous nanoparticles (ANPs) of <300 nm diameter using solvent/antisolvent nanoprecipitation, organic solvent removal, and spray drying was demonstrated previously on model compound ABT-530 with Copovidone and sodium dodecyl sulfate (anionic). In this work, nonionic surfactant d-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS, or TPGS) was used to prepare ANPs as a comparison. Characterization of ANPs by dynamic light scattering, filtrate potency assay, scanning electron microscopy, and differential scanning calorimetry revealed differences in surface properties of nanoparticles afforded by surfactants. This work demonstrates the importance of understanding the impact of the stabilizing agents on nanoparticle behavior when designing a high-drug-load amorphous formulation for poorly water-soluble compounds as well as the impact on redispersion.

Design of a Re-Dispersible High Drug Load Amorphous Formulation.

Amorphous solid dispersions (ASD) are a commonly used enabling formulation technology to drive oral absorption of poorly soluble drugs. To ensure adequate solid-state stability and dissolution characteristics, the ASD formulation design typically has ≤ 25% drug loading. Exposed to aqueous media, ASD formulations can produce drug-rich colloidal dispersion with particle size < 500 nm. This in situ formation of colloidal particles requires incorporation of excess excipients in the formulation. The concept of using engineered drug-rich particles having comparable size as those generated by ASDs in aqueous media is explored with the goal of increasing drug loading in the solid dosage form. Utilizing ABT-530 as model compound, a controlled solvent-antisolvent precipitation method resulted in a dilute suspension that contained drug-rich (90% (w/w)) amorphous nanoparticles (ANP). The precipitation process was optimized to yield a suspension containing < 300 nm ANP. A systematic evaluation of formulation properties and process variables resulted in the generation of dry powders composed of 1-8 µm agglomerates of nanoparticles which in contact with water regenerated the colloidal suspension having particle size comparable to primary particles. Thus, this work demonstrates an approach to designing a re-dispersible ANP based powder containing ≥90% w/w ABT-530 that could be used in preparation of a high drug load solid dosage form.

Assessing Physical Stability Risk Using the Amorphous Classification System (ACS) Based on Simple Thermal Analysis.

The purpose of this study is to develop a classification system utilizing milligram amounts of the compound for physical stability ranking of amorphous pharmaceuticals, which can be used as an early risk assessment tool for amorphous solid dispersion formulations. Simple thermal analysis utilizing a differential scanning calorimeter is used to characterize amorphous pharmaceuticals with respect to their molecular mobility and configurational entropy. Molecular mobility and configurational entropy are considered as two critical factors in determining the physical stability of amorphous phases. Theoretical arguments and numerical simulations suggest that the fragility strength parameter is a good indicator of the molecular mobility below Tg, and the heat capacity change at Tg is a good indicator of the configurational entropy. Using these two indicators, 40 structurally diverse pharmaceuticals with known physical stability were analyzed. Four classes of compounds are defined with class I being the most stable and class IV the least stable. The proposed amorphous classification system and methodology for estimating molecular mobility and configurational entropy provides an easily accessible framework to conduct early risk assessments related to physical stability challenges in developing amorphous formulations.

Understanding and managing the impact of HPMC variability on drug release from controlled release formulations.

The purpose of this study is to identify critical physicochemical properties of hydroxypxropyl methylcellulose (HPMC) that impact the dissolution of a controlled release tablet and develop a strategy to mitigate the HPMC lot-to-lot and vendor-to-vendor variability. A screening experiment was performed to evaluate the impacts of methoxy/hydroxypropyl substitutions, and viscosity on drug release. The chemical diversity of HPMC was explored by nuclear magnetic resonance (NMR), and the erosion rate of HPMC was investigated using various dissolution apparatuses. Statistical evaluation suggested that the hydroxypropyl content was the primary factor impacting the drug release. However, the statistical model prediction was not robust. NMR experiments suggested the existence of structural diversity of HPMC between lots and more significantly between vendors. Review of drug release from hydrophilic matrices indicated that erosion is a key aspect for both poorly soluble and soluble drugs. An erosion rate method was then developed, which enabled the establishment of a robust model and a meaningful HPMC specification. The study revealed that the overall substitution level is not the unique parameter that dictates its release-controlling properties. Fundamental principles of polymer chemistry and dissolution mechanisms are important in the development and manufacturing of hydrophilic matrices with consistent dissolution performance.

Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties.

Among the diverse sets of nicotinic acetylcholine receptors (nAChRs), the alpha7 subtype is highly expressed in the hippocampus and cortex and is thought to play important roles in a variety of cognitive processes. In this review, we describe the properties of a novel biaryl diamine alpha7 nAChR agonist, A-582941. A-582941 was found to exhibit high-affinity binding and partial agonism at alpha7 nAChRs, with acceptable pharmacokinetic properties and excellent distribution to the central nervous system (CNS). In vitro and in vivo studies indicated that A-582941 activates signaling pathways known to be involved in cognitive function such as ERK1/2 and CREB phosphorylation. A-582941 enhanced cognitive performance in behavioral models that capture domains of working memory, short-term recognition memory, memory consolidation, and sensory gating deficit. A-582941 exhibited a benign secondary pharmacodynamic and tolerability profile as assessed in a battery of assays of cardiovascular, gastrointestinal, and CNS function. The studies summarized in this review collectively provide preclinical validation that alpha7 nAChR agonism offers a mechanism with potential to improve cognitive deficits associated with various neurodegenerative and psychiatric disorders.

Thermodynamics, molecular mobility and crystallization kinetics of amorphous griseofulvin.

Griseofulvin is a small rigid molecule that shows relatively high molecular mobility and small configurational entropy in the amorphous phase and tends to readily crystallize from both rubbery and glassy states. This work examines the crystallization kinetics and mechanism of amorphous griseofulvin and the quantitative correlation between the rate of crystallization and molecular mobility above and below Tg. Amorphous griseofulvin was prepared by rapidly quenching the melt in liquid N2. The thermodynamics and dynamics of amorphous phase were then characterized using a combination of thermal analysis techniques. After characterization of the amorphous phase, crystallization kinetics above Tg were monitored by isothermal differential scanning calorimetry (DSC). Transformation curves for crystallization fit a second-order John-Mehl-Avrami (JMA) model. Crystallization kinetics below Tg were monitored by powder X-ray diffraction and fit to the second-order JMA model. Activation energies for crystallization were markedly different above and below Tg suggesting a change in mechanism. In both cases molecular mobility appeared to be partially involved in the rate-limiting step for crystallization, but the extent of correlation between the rate of crystallization and molecular mobility was different above and below Tg. A lower extent of correlation below Tg was observed which does not appear to be explained by the molecular mobility alone and the diminishing activation energy for crystallization suggests a change in the mechanism of crystallization.

A calorimetric investigation of thermodynamic and molecular mobility contributions to the physical stability of two pharmaceutical glasses.

The purpose of this work was to investigate the contribution of thermodynamics and mobility to the physical stability of two pharmaceutical glasses with similar glass transition temperatures (Tg), by comparing configurational thermodynamic quantities and molecular relaxation time constants (tau) at temperatures below Tg. Ritonavir and nifedipine were chosen as model glasses because they show excellent and poor physical stability, respectively. Although ritonavir and nifedipine have similar Tg values (50 and 46 degrees C, respectively), amorphous ritonavir is quite stable while nifedipine has been reported to crystallize at temperatures as low as 40 degrees C below Tg. Modulated temperature differential scanning calorimetry (MTDSC) was used to characterize both crystalline phases and freshly prepared glasses. The glasses were then annealed at Tg-Ta = 25 degrees C while monitoring the extent of relaxation and heat capacity change as a function of time via MTDSC. Configurational thermodynamic quantities (Gc, Hc, and Sc) and molecular relaxation time constants, tau, were calculated from the calorimetric data. Interestingly, the Gibbs free energy driving force for crystallization was nearly identical for the two compounds. The largest differences were found in the configurational entropy (Sc) values for the fresh glasses and in the Sc values over time. Configurational entropy values were approximately 50% higher for ritonavir. The tau values of freshly prepared glasses indicated that both materials had similar initial mobility at the annealing temperatures and the temperature dependence of tau was approximately Arrhenius, regardless of age. Although initial tau values were similar, the tau values after 3 days annealing were approximately sixfold greater for ritonavir. The relatively poor physical stability of nifedipine compared to ritonavir is attributed to both the lower entropic barrier to crystallization for fresh and annealed glass, and higher molecular mobility in aged glasses of nifedipine. These observations below Tg are consistent with the previous work on physical stability of amorphous pharmaceuticals performed above Tg.

Preparation and drug loading of poly(ethylene glycol)-block-poly(epsilon-caprolactone) micelles through the evaporation of a cosolvent azeotrope.

PURPOSE: The aim of this work was to study the assembly, drug loading, and stability of poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PEG-b-PCL) micelles. METHODS: Three PEG-b-PCL compositions with PCL number average molecular weights of 1000, 2500, and 4000 g/mol were used. The assembly of PEG-b-PCL micelles, induced by the addition of water to acetonitrile (ACN), was characterized with 1H nuclear magnetic resonance spectroscopy (1H-NMR) and dynamic light scattering (DLS) with and without the presence of fenofibrate, a poorly water-soluble drug. PEG-b-PCL micelles with encapsulated fenofibrate were prepared through the removal of a negative ACN-water azeotrope under reduced pressure. Fenofibrate content was measured using reverse-phase high-performance liquid chromatography (HPLC), whereas the kinetic stability of PEG-b-PCL micelles with and without encapsulated fenofibrate was evaluated using size exclusion chromatography (SEC). RESULTS: The critical water content (CWC), the water content at which amphiphilic block copolymer (ABC) micelle assembly begins, was determined using DLS and ranged from 10% to 30% water, depending on both PCL molecular weight and PEG-b-PCL concentration. As the water content was increased, the PEG-b-PCL unimers assembled into swollen structures with hydrodynamic diameters ranging from 200 to 800 nm. The 1H-NMR peaks associated with the PCL block exhibited line-broadening, following the addition of D2O, indicating that the PCL blocks reside in the core of the PEG-b-PCL micelle. With further addition of water, the PCL cores collapsed to form fairly monodisperse PEG-b-PCL micelles (20-60 nm). In the presence of fenofibrate, the CWC value was lowered, perhaps due to hydrophobic interactions of fenofibrate and the PCL block. Further addition of water and subsequent evaporation of the negative ACN-water azeotrope resulted in fenofibrate-loaded PEG-b-PCL micelles of under 50 nm. The extent of fenofibrate encapsulation was dependent on PCL block size. At a polymer concentration of 1.0 mg/ml, PEG-b-PCL (5000:4000) and (5000:2500) micelles could encapsulate more than 90% of the initial loading level of fenofibrate, whereas PEG-b-PCL (5000:1000) micelles encapsulate only 28%. SEC experiments revealed that PEG-b-PCL (5000:4000) and (5000:2500) micelles eluted intact, indicating kinetic stability, whereas PEG-b-PCL (5000:1000) micelles eluted primarily as unimers. CONCLUSIONS: PEG-b-PCL in ACN assembles with fenofibrate into drug-loaded polymeric micelles with the addition of water and the subsequent removal of a negative ACN-water azeotrope.

Phase transformation considerations during process development and manufacture of solid oral dosage forms.

The quality and performance of a solid oral dosage form depends on the choice of the solid phase, the formulation design, and the manufacturing process. The potential for process-induced solid phase transformations must be evaluated during design and development of formulations and manufacturing processes. This article briefly reviews the basic principles of polymorphism, defines the classes of phase transformation and the underlying transformation mechanisms, and discusses respective kinetic factors. The potential phase transformations associated with common unit operations employed in manufacturing solid oral dosage forms are highlighted. Specific examples are given to illustrate the importance of solid phases, and process-induced phase transitions in formulation and process development.

Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations.

Ritonavir is a large, lipophilic molecule that is practically insoluble in aqueous media and exhibits an exceedingly slow intrinsic dissolution rate. Although it has favorable lipophilicity, in vitro permeability studies have shown that ritonavir is a substrate of P-glycoprotein. Thus, the oral absorption of ritonavir could be limited by both dissolution and permeability, thereby making it a Class IV compound in the Biopharmaceutics Classification System. Because formulations rarely exert direct influence on local intestinal permeability, the effect of enhanced dissolution rate on oral absorption was explored. More specifically, poly(ethylene glycol) (PEG)-amorphous ritonavir solid dispersions were prepared with different drug loadings, and the in vitro and in vivo performances of the dispersions were evaluated. In vitro dissolution was conducted in 0.1N HCl with a USP Apparatus I. A crossover design was used to evaluate the oral bioavailability of amorphous dispersions relative to crystalline drug in beagle dogs. Intrinsic dissolution measurements of the two solid phases indicated a 10-fold improvement in intrinsic dissolution rate for amorphous ritonavir compared with the crystalline counterpart. In vitro dissolution of ritonavir depended on the solid phase as well as drug loading of the dispersion. In vivo study results indicate that amorphous solid dispersions containing 10-30% drug exhibited significant increases in area under the curve of concentration versus time (AUC) and maximum concentration (C(max)) over crystalline drug. For example, 10% amorphous dispersion exhibited increases of 22- and 13.7-fold in AUC and C(max), respectively. However, both in vitro dissolution and bioavailability decreased with increasing drug load, which led to the construction of a multiple Level C in vitro-in vivo relationship for this Class IV compound. The established relationship between in vitro dissolution and in vivo absorption can help guide formulation development.

Crystallization kinetics of amorphous nifedipine studied by model-fitting and model-free approaches.

The crystallization of amorphous nifedipine was studied using hot-stage microscopy (HSM), powder X-ray diffractometry (PXRD), and differential scanning calorimetry (DSC). The kinetic data obtained from DSC studies under isothermal and nonisothermal conditions were examined using both model-fitting and model-free approaches. Evaluation of 16 different models showed that model A4 (Avrami-Erofeev, n = 4) to be most appropriate for crystallization in the conversion range 0.05-0.80. This choice was based on the goodness of fit, the residual plots, and the guidance provided by the model-free approach. The model-free approach indicated that the activation energy decreases slightly as the crystallization proceeds. This variation of the activation energy with the extent of conversion determines the range of conversion over which a model can be fit, and the magnitude of the activation energy helps in the selection of the best model. The model-free approach gives much better predictions than the model of best fit and allows the experimental kinetic function to be numerically evaluated. At the early stage (alpha = 0-0.6), the numerically reconstructed model is almost identical to A4, but gradually approaches A3 (Avrami-Erofeev, n = 3) as the crystallization progresses (alpha = 0.6-0.8) and deviates from both models near the end of the reaction. This behavior may be explained by the relative contributions of nucleation and crystal growth at different stages of the reaction.

Model-free treatment of the dehydration kinetics of nedocromil sodium trihydrate.

The conventional model-fitting approach to kinetic analysis assumes a fixed mechanism throughout the reaction and therefore may be too simplistic for many solid-state reactions. Even for a reaction with a fixed mechanism, model fitting sometimes cannot identify the reaction model uniquely. The alternative model-free approach is sufficiently flexible to allow for a change of mechanism during the course of a reaction and therefore provides a more realistic treatment of solid-state reactions kinetics. The application of model-free analysis to solid-state dehydrations was investigated using the two consecutive dehydration reactions of nedocromil sodium trihydrate. The complexity of such reactions is illustrated by the variation of the activation energy as each dehydration proceeds. The 1st-step dehydration follows one-dimensional phase boundary kinetics until the fraction dehydrated reaches 0.75, and deviates from this model thereafter. The 2nd-step dehydration follows a mechanism intermediate between two- and three-dimensional diffusion that cannot be described by any of the common models. The model-free approach is clearly better than the model-fitting approach for understanding the details of these solid-state dehydration reactions.

Properties of rapidly dissolving eutectic mixtures of poly(ethylene glycol) and fenofibrate: the eutectic microstructure.

Poly(ethylene glycol) or PEG is an ideal inactive component for preparing simple binary eutectic mixtures because of its low entropy of fusion ( approximately 0.0076 J/mol-K), lower melting point (approximately 62 degrees C) compared to most pharmaceuticals, miscibility with drugs at elevated temperatures, and its covalent crystalline lattice. Implication of these physicochemical properties on eutectic crystallization and size reduction of the drug is discussed. Enhancement of the dissolution rate of a poorly soluble compound through the formation of PEG-drug eutectics was investigated using fenofibrate. Solid dispersions of PEG-fenofibrate when characterized, revealed that PEG and fenofibrate form a simple eutectic mixture containing 20-25%(w/w) fenofibrate at the eutectic point. Eutectic crystallization led to the formation of an irregular microstructure in which fenofibrate crystals were found to be less than 10 microm in size. Dissolution rate improvement of fenofibrate correlated with the phase diagram, and the amount of fenofibrate released from the dispersions that contained fenofibrate as a eutectic mixture was at least 10-fold higher compared to untreated fenofibrate. On aging, the dissolution rate of the dispersion containing 15%(w/w) fenofibrate in PEG remained unaltered. The results indicate that PEG-drug eutectic formation is a valuable option for particle size reduction and subsequent dissolution rate improvement.

Physical stability of amorphous pharmaceuticals: Importance of configurational thermodynamic quantities and molecular mobility.

This work relates the thermodynamic quantities (Gc, Hc, and Sc) and the molecular mobility values (1/tau) of five structurally diverse amorphous compounds to their crystallization behavior. The model compounds included: ritonavir, ABT-229, fenofibrate, sucrose, and acetaminophen. Modulated temperature DSC was used to measure the heat capacities as a function of temperature for the amorphous and crystalline phases of each compound. Knowledge of the heat capacities and fusion data allowed calculation of the configurational thermodynamic quantities and the Kauzmann temperatures (T(K)) using established relationships. The molecular relaxation time constants (tau) were then calculated from the Vogel-Tammann-Fulcher representation of the Adam-Gibbs model. Amorphous samples were heated at 1 K/min and a reduced crystallization temperature, defined as (Tc - Tg)/(Tm-Tg), was used to compare crystallization tendencies. Crystallization was observed for all compounds except ritonavir. The configurational free energy values (Gc) show that thermodynamic driving forces for crystallization follow the order: ritonavir > acetaminophen approximately fenofibrate > sucrose > ABT-229. The entropic barrier to crystallization, which is inversely related to the probability that the molecules are in the proper orientation, followed the order: ritonavir > fenofibrate > ABT-229 > acetaminophen approximately sucrose. Molecular mobility values, which are proportional to molecular collision rates, followed the order: acetaminophen > fenofibrate > sucrose > ABT-229 approximately ritonavir. Crystallization studies under nonisothermal conditions revealed that compounds with the highest entropic barriers and lowest mobilities were most difficult to crystallize, regardless of the thermodynamic driving forces. This investigation demonstrates the importance of both configurational entropy and molecular mobility to understanding the physical stability of amorphous pharmaceuticals.

Prediction of poly(ethylene) glycol-drug eutectic compositions using an index based on the van't Hoff equation.

PURPOSE: To define an index based on the van't Hoff equation that can be used as a screening tool for predicting poly(ethylene) glycol (PEG)-drug eutectic composition. METHODS: Phase diagrams of PEG with ritonavir, ibuprofen, fenofibrate. naproxen, and griseofulvin were constructed using differential scanning calorimetry, hot stage microscopy and powder X-ray diftractometry. Previously reported phase diagrams were also used to test the predictive capability of the index. RESULTS: This work shows that a modified van't Hoff equation can be used to model the drug liquidus line of these phase diagrams. The slope of the liquidus line depends on the melting point (T(f)d) and heat of fusion (deltaH(f)d) of the drug and describes the initial rate at which the eutectic or monotectic point is approached. Based on this finding, a dimensionless index Ic was defined. The index can be calculated from the melting points of the pure components and heat of fusion of the drug. In addition to the compounds listed above, the index was found to predict the eutectic composition for flurbiprofen, temazepam and indomethacin. These compounds range over 150 degrees C in T(f)d, and from 25-65 kJ/mole in deltaH(f)d. CONCLUSION: Using Ic the approximate eutectic composition for eight different compounds was predicted. The index provides a useful screening tool for assessing the maximum drug loading in a drug-polymer eutectic/monotectic formulation.