Preparation and advanced characterization of highly drug-loaded, 3D printed orodispersible tablets containing fluconazole.

Due to the possibility of designing various spatial structures, three-dimensional printing can be implemented in the production of customized medicines. Nevertheless, the use of these methods for the production of dosage forms requires further optimization, understanding, and development of printouts' quality verification mechanisms. Therefore, the goal of our work was the preparation and advanced characterization of 3D printed orodispersible tablets (ODTs) containing fluconazole, printed by the fused deposition modeling (FDM) method. We prepared and analyzed 7 printable filaments containing from 10% to 70% fluconazole, used as model API. Obtaining a FDM-printable filament with such a high API content makes our work unique. In addition, we confirmed the 12-month stability of the formulation, which, to our knowledge, is the first study of this type. Next, we printed 10 series of porous tablets containing 50 mg of API from both fresh and stored filaments containing 20 %, 40 %, or 70 % fluconazole. We confirmed the high quality and precision of the printouts using scanning electron microscopy. The detailed analysis of the tablets' disintegration process included the Pharmacopeial test, but also the surface dissolution imaging analysis (SDI) and the test simulating oral conditions performed in own-constructed apparatus. For each composition, we obtained tablets disintegrating in less than 3 min, i.e., meeting the criteria for ODTs required by the European Pharmacopeia. The filaments' storage at ambient conditions did not affect the quality of the tablets. All printed tablets released over 95% of the fluconazole within 30 min. Moreover, the printouts were stable for two weeks.

Continuous Manufacture and Scale-Up of Theophylline-Nicotinamide Cocrystals.

The aim of the study was the manufacturing and scale-up of theophylline-nicotinamide (THL-NIC) pharmaceutical cocrystals processed by hot-melt extrusion (HME). The barrel temperature profile, feed rate and screw speed were found to be the critical processing parameters with a residence time of approximately 47 s for the scaled-up batches. Physicochemical characterization using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction of bulk and extruded materials revealed the formation of high purity cocrystals (98.6%). The quality of THL-NIC remained unchanged under accelerated stability conditions.

Application of Focus Variation Microscopy and Dissolution Imaging in Understanding the Behaviour of Hydrophilic Matrices.

Hydrophilic matrix systems can be found in a wide range of extended release pharmaceutical formulations. The main principle of these systems is that upon contact with water, the hydrophilic component swells to form a hydrated gel layer which controls drug release. The following work demonstrates an explorative study into the use of dissolution imaging and focus variation microscopy with hydrophilic polymers. This study investigated the surface properties of xanthan gum (XG), polyethylene oxide (PEO), and hypromellose (hydroxypropyl methylcellulose, HPMC) compacts with each of these three hydrophilic polymers from one of each classification of natural, semi-synthetic, or synthetic polymer using a focus variation instrument. The auto correlation length (Sal) showed all surface profiles from the compacts displayed a value below 0.1 mm, indicating that only high frequency components (i.e., roughness) were considered and that the analysis had been successful. The developed interfacial area ratio (Sdr) displayed values below 5% in line with ISO guidelines for all the polymers studied with their texture aspect ratio values (Str) > 0.5, indicating uniformity of the surfaces of the produced compacts. Of the various parameters studied, areal material ratio (Smr2) predicted XG to wet and hydrate quicker than PEO, with PEO also wetting and hydrating quicker than the HPMC. The dissolution imaging and initial swelling studies proved to concur with the findings from the areal material ratio (Smr2) parameter, suggesting porosity was not an indicator for the ease with which water ingress occurs. This study suggests the Smr2 surface parameter to potentially predict wetting and initial hydration of hydrophilic polymers, however care should be taken as this study consists of a selected number of hydrophilic polymers.

An interlaboratory investigation of intrinsic dissolution rate determination using surface dissolution.

The purpose of this study was to conduct an interlaboratory ring-study, with six partners (academic and industrial), investigating the measurement of intrinsic dissolution rate (IDR) using surface dissolution imaging (SDI) equipment. Measurement of IDR is important in pharmaceutical research as it provides characterising information on drugs and their formulations. This work allowed us to assess the SDI's interlaboratory performance for measuring IDR using a defined standard operating procedure (see supporting information) and six drugs assigned as low (tadalafil, bromocriptine mesylate), medium (carvedilol, indomethacin) and high (ibuprofen, valsartan) solubility compounds. Fasted State Simulated Intestinal Fluid (FaSSIF) and blank FaSSIF (without sodium taurocholate and lecithin) (pH 6.5) were used as media. Using the standardised protocol an IDR value was obtained for all compounds and the results show that the overall IDR rank order matched the solubility rank order. Interlaboratory variability was also examined and it was observed that the variability for lower solubility compounds was higher, coefficient of variation >50%, than for intermediate and high solubility compounds, with the exception of indomethacin in FaSSIF medium. Inter laboratory variability is a useful descriptor for understanding the robustness of the protocol and the system variability. On comparison to another published small-scale IDR study the rank ordering with respect to dissolution rate is identical except for the high solubility compounds. This results indicates that the SDI robustly measures IDR however, no recommendation on the use of one small scale method over the other is made.

Development of a novel method utilising dissolution imaging for the measurement of swelling behaviour in hydrophilic matrices.

A variety of imaging techniques are currently used within the field of pharmaceutics to help understand and determine a wide range of phenomena associated with drug release from hydrophilic matrix tablets. This work for the first time aims at developing an appropriate testing imaging methodology using a surface dissolution imaging instrument (SDI2) for determining the swelling of whole compacts using hypromellose as a model hydrophilic matrix former. The influence of particle morphology (CR and DC grades) and two compressional forces (5 and 15 kN) on the initial swelling behaviour of hypromellose were investigated. The results showed that a lower absorbance of 50 mAu with a wider measurement zone proved successful in determining the edge of the gel layer and growth measurements in real-time with high level of details under flow. Despite the differences in the morphology of the grades of hypromellose tested, it was however discovered that gel growth was statistically similar between them which may be attributed to their similar chemistry. This novel method also highlighted differences in the hydrated polymer's appearance which may have been as a result of differences in porosity and solid fraction. This information is of great importance to a formulator as gel growth plays a crucial role in determining drug release from polymer compacts.

Effect of preparation method on the surface properties and UV imaging of indomethacin solid dispersions.

This work explores the use of UV imaging in solid dispersion systems. Solid dispersions are one of the common strategies used in improving the dissolution of poorly soluble drugs. Three manufacturing techniques (spray drying (SD), freeze drying (FD) and homogenising (HG)) are investigated. Differential Scanning Calorimetry (DSC) and X-Ray Powder Diffraction (XRPD) was used in characterising the solid dispersions. Advanced imaging was implemented to give an insight into how these solid dispersions performed. The DSC and XRPD results showed that all three methods and the various ratios studied produced amorphous solid dispersions. Ultra-Violet (UV) imaging of the pseudo Intrinsic Dissolution Rate (IDR) deduced only two samples to have superior pseudo IDR values to the IDR of the parent drug indomethacin (INDO). The whole dose imaging of the capsule formulation however showed all the samples (SD, FD and HG) to have superior dissolution to that of INDO which was in contrast to the IDR results. The UV images obtained from the determination of the pseudo IDR also showed a phenomenon the authors are reporting for the first time where increased polymer (Soluplus) content produced "web-like" strands that migrated to the top of the quartz cell which may have been responsible for the low pseudo IDR values. The authors also report for the first time using this UV imaging technique, the tip of a capsule coming off for drug to go into solution. The area under the curve suggested the best five samples dissolution wise to be 1:3 SD > 1:1 HG > 1:1 SD > 1:3 FD > 1:3 HG meaning a ratio of INDO to SOL in these dispersion of up to 1:3 being sufficient to produce significant dissolution increases. The developed interfacial (surface) area ratio (Sdr) highlighted how the surface area of the IDR compacts varied between the batches, in particular highlighting larger surface area gains for the FD and HG compacts. A choice of instrumentation/techniques to use in making solid dispersions may well come down to cost or instrument availability for a formulator as all three techniques were successful in improving the dissolution of indomethacin. This work thus highlights the importance of having both complimentary IDR and whole dosage imaging techniques in giving a better understanding of solid dispersion systems.

Direct imaging of the dissolution of salt forms of a carboxylic acid drug.

The optimisation of the pharmaceutical properties of carboxylic acid drugs is often conducted by salt formation. Often, the salt with the best solubility is not chosen due to other factors such as stability, solubility, dissolution and bioavailability that are taken into consideration during the preformulation stage. This work uses advanced imaging techniques to give insights into the preformulation properties that can aid in the empirical approach often used in industry for the selection of salts. Gemfibrozil (GEM) was used as a model poorly soluble drug. Four salts of GEM were made using cyclopropylamine (CPROP), cyclobutylamine (CBUT), cyclopentylamine (CPENT) and cyclohexylamine (CHEX) as counterions. DSC, XRD and SEM were used to confirm and characterise salt formation. IDR obtained using UV-imaging up to 10 min for all the salts showed that an increase in the chain length of the counterion caused a decrease in the IDR. Past the 10 min mark, there was an increase in the IDR value for the CPROP salt, which was visualised using UV-imaging. The developed interfacial (surface) area ratio (Sdr) showed significant surface gains for the compacts. Full dosage form (capsule) imaging showed an improvement over the GEM for all the salts with an increase in chain length of the counterion bringing about a decrease in dissolution which correlated with the obtained UV-imaging IDR data.

Variable-focus microscopy and UV surface dissolution imaging as complementary techniques in intrinsic dissolution rate determination.

This work reports a novel approach to the assessment of the surface properties of compacts used in Surface Dissolution Imaging (SDI). SDI is useful for determining intrinsic dissolution rate (IDR), an important parameter in early stage drug development. Surface topography, post-compaction and post-SDI run, have been measured using a non-contact, optical, three-dimensional microscope based on focus variation, the Alicona Infinite Focus Microscope, with the aim of correlating the IDRs to the surface properties. Ibuprofen (IBU) was used as a model poorly-soluble drug. DSC and XRD were used to monitor possible polymorphic changes that may have occurred post-compaction and post-SDI run. IBUs IDR decreased from 0.033mg/min/cm2 to 0.022mg/min/cm2 from 10 to 20min, respectively, during the experiment. XRD and DSC showed no form changes during the SDI run. The surface topography images showed that a distinct imprint was embossed on the surfaces of some compacts which could affect IDRs. Surface parameter values were associated with the SDI experiments which showed strong correlations with the IDR values. The variable-focus microscope can be used as a complimentary tool in the determination of IDR values from the SDI.