The influence of input material properties on hot melt granules prepared using a counter-rotating batch mixer.

OBJECTIVE: The objective of this study was to develop a method that enabled granulation in a counter-rotating batch mixer to emulate large scale dry twin screw granulation trials. METHODS: Four granulations were prepared using counter rotating batch mixing for formulations containing a mixture of different particle sizes of the API (70% w/w) and polymer (30% w/w). Milled theophylline (MTHF; fine API) was blended with coarse hydroxypropyl cellulose (HPC MF; coarse polymer), theophylline (THF; coarse API) with fine hydroxypropyl cellulose (HPC EXF, fine polymer), and the other two formulations consisted of both components in the blend being fine or coarse. RESULTS: The formulations selected for granulation had the lowest friction coefficient, f, as a function of drug load determined by the iShear® powder flow rheometer. Despite the non-uniform chaotic and random nature of thermal granulation, each formulation granulated reproducibly, though the evolution for each was different. CONCLUSION: This work highlighted that, firstly it is possible to measure plastic and frictional energy dissipation as product temperature. Secondly, granule growth and density were found to be proportional to the onset of polymer molecular mobility activated by the heat liberated from interparticle velocity differences via mechanical work (torque) required to move agglomerates through the mixer for the duration of each run.

A comparative assessment of nanocomposites vs. amorphous solid dispersions prepared via nanoextrusion for drug dissolution enhancement.

Nanoextrusion was used to produce extrudates of griseofulvin, a poorly water-soluble drug, with the objective of examining the impact of drug particle size and polymeric matrix type-size of the extrudates on drug dissolution enhancement. Hydroxypropyl cellulose (HPC) and Soluplus® were used to stabilize wet-milled drug suspensions and form matrices of the extrudates. The wet-milled suspensions along with additional polymer (HPC/Soluplus®) were fed to a co-rotating twin-screw extruder, which dried the suspensions and formed various extrudates. The extrudates were dry-milled and sieved into samples with two different sizes. A wet-milled suspension was also spray-dried in comparison to nanoextrusion. Due to differences in polymer-drug miscibility, two forms of the drug were prepared: extrudates with nano/micro-crystalline drug particles dispersed in the HPC matrix as a secondary phase (nano/microcomposites) and extrudates with amorphous drug molecularly dispersed within the Soluplus® matrix (amorphous solid dispersion, ASD). Under non-supersaturating conditions in the dissolution medium, drug nanocrystals in the HPC-based nanocomposites dissolved faster than the amorphous drug in Soluplus®-based ASD. While smaller extrudate particles led to faster drug release for the ASD, such matrix size effect was weaker for the nanocomposites. These findings suggest that nanocrystal-based formulations could outperform ASDs for fast dissolution of low-dose drugs.

Improving the API dissolution rate during pharmaceutical hot-melt extrusion I: Effect of the API particle size, and the co-rotating, twin-screw extruder screw configuration on the API dissolution rate.

The dissolution rate of the active pharmaceutical ingredients in pharmaceutical hot-melt extrusion is the most critical elementary step during the extrusion of amorphous solid solutions - total dissolution has to be achieved within the short residence time in the extruder. Dissolution and dissolution rates are affected by process, material and equipment variables. In this work, we examine the effect of one of the material variables and one of the equipment variables, namely, the API particle size and extruder screw configuration on the API dissolution rate, in a co-rotating, twin-screw extruder. By rapidly removing the extruder screws from the barrel after achieving a steady state, we collected samples along the length of the extruder screws that were characterized by polarized optical microscopy (POM) and differential scanning calorimetry (DSC) to determine the amount of undissolved API. Analyses of samples indicate that reduction of particle size of the API and appropriate selection of screw design can markedly improve the dissolution rate of the API during extrusion. In addition, angle of repose measurements and light microscopy images show that the reduction of particle size of the API can improve the flowability of the physical mixture feed and the adhesiveness between its components, respectively, through dry coating of the polymer particles by the API particles.

Crystallization of poly(ethylene oxide) with acetaminophen--a study on solubility, spherulitic growth, and morphology.

A simple, sensitive, efficient, and novel method analyzing the number of spherulitic nuclei was proposed to estimate the solubility of a model drug acetaminophen (APAP) in poly(ethylene oxide) (PEO). At high crystallization temperature (323 K), 10% APAP-PEO had the same low number of spherulitic nuclei as pure PEO, indicating that APAP and PEO were fully miscible. At low crystallization temperature (303 K), the number of nuclei for 10% APAP-PEO was significantly higher, suggesting that APAP was oversaturated and therefore recrystallized and acted as a nucleating agent. Based on the results obtained, the solubility of APAP in PEO is possibly between the concentration of 0.1% and 1% at 303 K. The spherulitic growth rate G of PEO was found to decrease with increasing APAP concentration, suggesting that APAP is most likely functioning as a chemical defect and is either rejected from or included in the PEO crystals during chain folding. APAP could possibly locate in the inter-spherulitic, inter-fibrillar, inter-lamellar, or intra-lamellar regions of PEO. At 323 K, the morphology of 10% APAP-PEO is more dendritic than spherulitic with large unfilled space in between dendrites and spherulites, which is a sign of one or the combination of the four modes of segregation. An extensive spherulitic nucleation and growth kinetics study using the classical theoretical relationships, for example, the Hoffman-Lauritzen (HL) and Avrami theories, was conducted. Both microscopic and differential scanning calorimetric (DSC) analysis yielded similar values for the nucleation constant Kg as well as the fold surface free energy σe and work of chain folding q. The values of σe and q increased with APAP concentration, indicating that the chain folding of PEO was hindered by APAP.

Prediction of acetaminophen's solubility in poly(ethylene oxide) at room temperature using the Flory-Huggins theory.

Solid dispersion technologies such as hot-melt extrusion and spray drying are often used to enhance the solubility of poorly soluble drugs. The biggest challenge associated with solid dispersion systems is that amorphous drugs may phase-separate from the polymeric matrix and recrystallize during storage. A more fundamental understanding of drug-polymer mixtures is needed for the industry to embrace the solid dispersion technologies. In this study, a theoretical model based on Flory-Huggins lattice theory was utilized to predict the solubility of a model drug acetaminophen (APAP) in a semi-crystalline polymer poly(ethylene oxide) (PEO) at 300 K. The interaction parameter χ was calculated to be -1.65 from the depression of drug's melting temperature determined from rheological and differential scanning calorimetry analysis. The equilibrium solubility in amorphous PEO was estimated to be 11.7% at 300 K. Assuming no APAP molecules dissolve in the crystalline part of PEO, the adjusted theoretical solubility is around 2.3% considering PEO being 80% crystalline. The solubility of APAP in PEG 400 was calculated to be 14.6% by using the same χ value, close to the experimental measurement 17.1%. The drug's solubility could be altered noticeably by the change of both χ and polymer molecular weight. The study also suggests that the depression of drug's melting point is a good indicator for preliminary polymer screening. The polymer that reduces the melting point the most is likely to be most miscible with the drug.

Miscibility studies of indomethacin and Eudragit® E PO by thermal, rheological, and spectroscopic analysis.

The objective of this study is to understand the underlying mechanisms responsible for the superior stability of indomethacin (INM)-Eudragit® E PO (E PO) system by exploring the miscibility and intermolecular interactions through the combination of thermal, rheological, and spectroscopic analysis. The zero shear-rate viscosity drops monotonically with the increase of INM concentration at 145 °C, suggesting that E PO and INM form a solution and the small molecular drug acts as a plasticizer. Flow activation energy was calculated from the viscosity data at different temperature. The glass transition temperature (T(g)) of the mixture at different composition was determined using differential scanning calorimetry. The T(g) and flow activation energy peak at the INM concentration around 60%-70%. Fourier transform infrared analysis provided direct evidence for the intermolecular ionic interactions, which may disrupt the dimer formation of amorphous INM. The study explained the superior stability of INM-E PO mixtures, and demonstrated that a combination of thermal, rheological, and spectroscopic technologies can help us to obtain a full picture of the drug-polymer interactions and to determine the formulation and processing conditions.

Rheological study of the mixture of acetaminophen and polyethylene oxide for hot-melt extrusion application.

There is a growing interest of extrusion drug and polymer together to manufacture various solid dosages. In those cases, the drug's release profiles are greatly affected by the miscibility of two materials. The goal of this study is to test the drug's solubility in molten polymer and obtain the mixture's rheological properties for the purpose of optimizing the extrusion process. The dynamic and steady viscosities of APAP-PEO mixture were determined using oscillatory and capillary rheometers. The curves of viscosity vs. drug loading generally have a "V" shape, and the minimal point gives the APAP's solubility in PEO. The test results suggest that different dynamic methods lead to essentially the same solubility data. At high shear rates, the mixtures show shear thinning behavior and the viscosity becomes less sensitive to the drug loading. In other words, it is desirable to use a low shear rate in order to deduce the drug's solubility in polymer from the viscosity data. On the other hand, viscosity data at high shear rates are more representative of the materials' rheological properties during extrusion.

Determination of acetaminophen's solubility in poly(ethylene oxide) by rheological, thermal and microscopic methods.

A drug's solubility in a polymeric excipient is an important parameter that dictates the process window of hot-melt extrusion (HME) and product stability during storage. However, it is rather challenging to experimentally determine the solubility and there is very few published work in this field. In this study, the solubility of a model drug acetaminophen (APAP) in a pharmaceutical grade polymer poly(ethylene oxide) (PEO) at HME processing temperature was measured utilizing rheological analysis, hot-stage microscopy and differential scanning calorimetry (DSC). The results from three methods were consistent and the solubility was found to increase from 14% at 80°C to 41% at 140°C. The apparent drug solubility at room temperature was estimated to be less than 10% through glass transition temperature (T(g)) measurement using DSC and dynamic mechanical thermal analysis (DMTA). A "phase diagram" was constructed based on the experimental data and could be explored to design the HME process and formulation. Very few assumptions were made in the experimental study and result analysis, and the methods described here can be applied to investigate other drug-polymer systems to obtain the important thermodynamic data.

Solid dispersion of acetaminophen and poly(ethylene oxide) prepared by hot-melt mixing.

In this study, a model drug, acetaminophen (APAP), was melt mixed with poly(ethylene oxide) (PEO) using a Brabender mixer. APAP was found to recrystallize upon cooling to room temperature for all the drug loadings investigated. Higher drug loading leads to faster recrystallization rate. However, the morphology of the recrystallized drug crystals is identical in samples with different drug loadings and does not change with the storage time. To adjust the drug's dissolution rate, nanoclay Cloisite 15A and 30B were added into the binary mixture. The presence of either of the nanoclay dramatically accelerates the drug's recrystallization rate and slows down the drug's releasing rate. The drop of the releasing rate is mainly due to the decrease of wettability, as supported by the contact angle data. Data analysis of the dissolution results suggests that the addition of nanoclays changes the drug's release mechanism from erosion dominant to diffusion dominant. This study suggests that nanoclays may be utilized to tailor the drug's releasing rate and to improve the dosage form's stability by dramatically shortening the lengthy recrystallization process.

Effects of extrusion process parameters on the dissolution behavior of indomethacin in Eudragit E PO solid dispersions.

This work studied the dissolution of indomethacin (INM) into polymer excipient Eudragit E PO (E PO) melt at temperatures lower than the melting point of INM using a laboratory-size, twin-screw counter-rotating batch internal mixer. The effects of three process parameters--set mixer temperature, screw rotating speed and residence time--were systematically studied. Scanning electron microscopy (SEM), optical microscopy (OM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR) were employed to investigate the evolution of INM's dissolution into the molten excipient. Differential scanning calorimetry (DSC) was used to quantitatively study the melting enthalpy evolution of the drug. The results showed that the dissolution rate increased with increasing the mixer set temperature, or the screw rotating speed. It was concluded that the dissolution of the drug in the polymer melt is a convective diffusion process, and that laminar distributive mixing can significantly enhance the dissolution rate. More importantly, the time needed for the drug to dissolve inside the molten polymer and the typical residence time for an extrusion process fall in the same range.