Film coating process development and applied film quality have been in the focus of the pharmaceutical industry for decades. Many techniques have been used to investigate and characterise complex film coating structures. Recently, terahertz pulsed imaging (TPI) has been introduced to study and understand the quality of film coatings. In this study, the effect of two different film-coaters , a fluid bed (Combi Coata, Model CC1/LAB, Niro Atomizer, Denmark) and a drum coater (Hi-Coater, HCT 20, Lödige Mascinenbau GmbH, Germany) on the applied film quality was determined by TPI (TPI imaga 2000, TeraView Ltd, Cambridge, UK). In addition to the coating application under recommended conditions, stress conditions were applied and investigated; e.g. high spray rate, simulated nozzle block during the coating process, and varying curing times after coating. From the terahertz time-domain waveforms, maps of the terahertz electricfield peak strength (TEFPS), interface index (TII) and coating thickness (CT) were successfully derived. SEM was used as a complimentary technique to increase the insight into the various coating characteristics. The results showed lower TEFPS values for samples coated by the fluid bed device, indicating a rougher coating surface than samples coating by the drum coater. Although the amount of coating applied was found to be the same, the mean CT for the fluid bed coated samples was higher. Furthermore, it was possible to distinguish an interface between the subsequent coating layers in the CT maps (generated by a coating liquid application stop), which couldn't be resolved by SEM for all samples. The different process conditions in both pieces of equipment are considered to be reason for this observation, as well as the difference found in the TII values (interface coating/core) for tablets coated by the two methods, respectively. In good agreement with previous studies, the overall thickness of the coating layer was systematically thinner around the centre band compared to the top and bottom surfaces. TPI can be considered to be a sophisticated PAT tool for gathering information, and increasing the understanding of complex film coating structures.

Surface phenomena were found to play a distinct role in performance of amorphous celecoxib solid dispersion (ACSD) which comprised of amorphous celecoxib (A-CLB), polyvinylpyrrolidone (PVP) and meglumine (MEG) at 7:2:1 weight ratio. In aqueous media, spray dried ACSD powder filled capsules displayed non-dispersible plug formation, due to cohesive interfacial interactions, that resulted in poor dissolution performance. Additionally, the free surface of ACSD predisposed it to faster devitrification under environmental stress and reduced its shelf life stability. Based on these findings, surface modification was evaluated as a means for its formulation design. Barrier coated-amorphous CLB solid dispersion layered particles (ADLP) were developed by Wurster process, using microcrystalline cellulose as substrate and polyvinyl alcohol (PVA), inulin and polyvinyl alcohol phthalate (PVAP) as coating excipients (at 3% w/w). In aqueous media, barrier coated-ADLP filled capsules were able to preclude the unfavorable interfacial interaction of amorphous particles, and achieved rapid dispersibility and high drug release, in comparison to uncoated ADLP and spray dried ACSD capsules. Physical stability under 25 °C/75% RH and 40 °C/75% RH open conditions indicated crystallization inhibition by 2 to 10-fold (cf. uncoated ADLP) and 9 to 50-fold (cf. spray dried ACSD) with barrier efficiency in the order of inulin

Amorphous solid dispersions (ASDs) offer a means to enhance oral bioavailability of poorly water soluble drugs. However, poor dissolution performance is one of the major challenges encountered in design of ASD based drug products. This study attempts to understand the role of solid-liquid interactions in dissolution behavior of an encapsulated ASD. Capsule dissolution of a molecularly interacting amorphous celecoxib solid dispersion (ACSD), comprising of amorphous celecoxib (A-CLB), polyvinylpyrrolidone (PVP) and meglumine (7:2:1 w/w), displayed non-dispersible plug formation, resulting in fall in the dissolution advantage. The solid dispersion displayed suppressed drug recrystallization during dissolution, studied using XRPD and DSC, and thus it was not the major contributor to this phenomenon. Also, evaluation of physical mixture of ACSD components (PM-ACSD) negated the role of PVP binder properties. Further, FTIR analysis of wet samples revealed that PVP component of ACSD exhibited partial bonding with water (shift of PVP carbonyl stretch from 1658 to 1654 cm^-1) as compared to that shown by PM-ACSD (shift from 1658 to 1646 cm^-1). This indicated formation of water-PVP-A-CLB hydrogen bond interlinks during ACSD dissolution. Consequently, these interactions graduated to interparticle level. Measurement of crushing strength for dry and hydrated compacts, using texture analysis, showed 7-fold increase in ACSD compact strength as compared to 3-fold for PM-ACSD compact. The findings suggested a significant impact of intermolecular interactions of the solid dispersion on its dosage form drug release, which (i) altered PVP's functionality and (ii) promoted interfacial cohesive interactions via water mediated hydrogen bonds, resulting in solid mass agglomeration. The study emphasis on understanding surface interactions occurring during dissolution, to aid in rationalized design of ASD based drug products.

Introduction: Colistin, a cyclic polypeptide linked to a fatty acyl tail, is an old antibiotic with potential toxicity when administered intravenously; however, for treating lung infections, dry powder inhalers (DPIs) have potential to deliver high doses directly to the site of infection. This study has examined the potential to engineer microparticles of colistin, with optimised surface energy, to create particles for effective use in DPIs. Methods: Spray dried colistin sulphate powders were obtained using a Buchi Mini-Spray Drier 190. Inverse Gas Chromatography (IGC) was used to determine the surface energies of the different particles. In vitro dispersion efficiency was measured by aerosolising into a twin stage impinger. Results and Discussion: Spray drying colistin increased the number of inhalable particles (< 6.5 µm) from 23.6% to 78%, providing a substantial improvement in the particle size distribution for delivery to the lower lung.This contributed to the increase in fine particle fraction (FPF) significantly (p< 0.001) from 15 % to 39 % when dispersed from a common commercial device. All spray dried formulations have a significantly higher (p < 0.001) fine particle fraction percentage than colistin as received. IGC surface energy measurements found there is a significantly lower (p < 0.001) total surface energy for all formulations after spray drying when compared to the colistin as received. This was proposed to be due to the peptide's surface active properties. It is further proposed that there is a relationship between the total surface energy and aerosolisation performance, as the total surface energy decreases the FPF increases. Conclusions: This study provides support for the development of an inhalable colistin dry powder formulation engineered via spray drying, that delivers high aerosolisation efficiency from a simple passive inhaler device. The IGC measurement provides evidence to support the surface self-assembly hypothesis for this peptide, that may account for the apparent high FPF.

Background: Active coating is an important unit operation in the pharmaceutical industry. The quality, stability, safety and performance of the final product largely depend on the amount and uniformity of coating applied. Active coating is challenging regarding the total amount of coating and its uniformity. Consequently, there is a strong demand for tools, which are able to monitor and determine the endpoint of a coating operation. In previous work, it was shown that Raman spectroscopy is an appropriate process analytical tool (PAT) to monitor an active spray coating process in a pan coater [1]. Using a multivariate model (Partial Least Squares) the Raman spectral data could be correlated with the coated amount of the API diprophylline. While the multivariate model was shown to be valid for the process in a mini scale pan coater (batch size: 3.5kg cores), the aim of the present work was to prove the robustness of the model by transferring the results to tablets coated to a micro scale pan coater (0.5kg). Method: Coating experiments were performed in both, a mini scale and a micro scale pan coater. The model drug diprophylline was coated on placebo tablets. The multivariate model, established for the process in the mini scale pan coater, was applied to the Raman measurements of tablets coated in the micro scale coater for 6 different coating levels. Then, the amount of coating, which was predicted by the model, was compared with measurements using UV spectroscopy. Results: For all the 6 coating levels the predicted coating amount was equal to the amounts obtained by UV spectroscopy within the statistical error. Thus it was possible to predict the total coating amount with an error smaller than 3.6%. The root mean square of errors for calibration and prediction (RMSEC and RMSEP) was 0.335mg and 0.392mg which means that the model's predictive power is not dependent on the scale or the equipment. Conclusion: The scale-down experiment showed that it was possible to transfer the model developed on a mini scale coater to a micro scale coater. References: [1] J. Müller et al., Feasibility of Raman spectroscopy as PAT tool in active coating, Drug Dev Ind Pharm (2010) 36, 234-243. Acknowledgment: This work was supported by TÁMOP-4.2.1/B-09/1/KONV-2010-0005(Hungary), P-MÖB/817 (Hungary) and DAAD Project PPP Ungarn 50430305 (Germany).

Introduction: Protein aggregation and its reversibility over time has been measured for a number of protein systems by Taylor dispersion analysis (TDA). This technique has many advantages over the conventional techniques currently employed; including its fast analysis times, large concentration range, and nanolitre sample sizes. Here the results obtained by TDA are compared to those obtained from dynamic light scattering (DLS). Materials and Methods: The ActiPix D100 employs UV area imaging and Taylor dispersion analysis (TDA) for determining diffusion coefficients and hydrodynamic radii of proteins in solution. The detector monitors broadening of a band of a therapeutic protein injected into a stream of buffer solution being driven through a fused-silica capillary. The band is imaged at two windows, the first on entry to and the second on exit from a loop in the capillary. The hydrodynamic radius follows from the measured differences between peak times and variances at the two windows. This technique was used to analyse various unstressed and stressed BSA samples over periods of time. The results were compared to those obtained from DLS and thermal methods. Results and Discussion: Hydrodynamic radius results obtained using TDA were in good correlation to those obtained using DLS. TDA and DLS both indicated that over time some aggregates were resolubilised and that the aggregate level had decreased, however DLS was less sensitive than TDA to these subtle changes. TDA was also shown to be more advantageous for measuring aggregation given it is not as susceptible to large particulates affecting the results as was the case with the DLS. Conclusions: Results for these samples indicate good correlation between the techniques for investigating protein aggregation behaviour. The ability to quantify accurately aggregate levels is being explored. TDA showed notable advantages over DLS when looking at solutions containing large particulates.

Historically, traditional dissolution devices have been performing measurements away from the solid-liquid interface and drawing conclusions on performance. By relocating measurements to the interface using a two dimensional orthogonal imager of a laminar flow through device, significantly more insight can be found about the intestinal surface concentration, in-situ surface pH, and amount lost from elimination. Having this information early in development provides formulators with better insight into optimum dosage and form.

Introduction: Crystal engineering is of great interest for many drug manufacturers in order to improve their products. A large number of active pharmaceutical ingredients (APIs) are poorly water soluble affecting the bioavailability, likewise they can have challenging physical properties such as unfavourable particle shape (e.g. needles) and surfaces affecting powder flowability and mixability. By designing crystals with optimized particle size and shape the API performance can be improved. Objective: To investigate the modified crystallization behaviour of nitrofurantoin monohydrate in presence of amide/lactam containing additives. Method: Nitrofurantoin was chosen as a model API as it is poorly water soluble and it forms needle-shaped crystals in aqueous environment. Nitrofurantoin was crystallized using evaporate crystallization from acetone/water mixtures on glasslides in presence of additives. Following polymers and monomers were used as additives: poly(N-isopropyl acrylamide) (PNIPAM), polyvinylpyrrolidone (PVP), Soluplus® (SOL), N-isopropyl acrylamide (NIPAM), dimethylacetamide (DMAA) and N-methylpyrrolidone (NMP). Optical microscope was used to analyse the crystals. Results: The crystal morphology of nitrofurantoin monohydrate can be significantly modified when it is crystallized in presence of PNIPAM, PVP and SOL, resulting in crystals with significant smaller particle size and intense branched growth compared to the needle-shaped crystals achieved without additives. Presence of SOL results in smaller crystals than presence of PNIPAM and PVP. Presence of NIPAM, DMAA and NMP were not found to affect the crystal morphology. The molecular size of the additive seems to have a key role in modifying the crystal morphology, indicating the dentrictic crystal growth could be related to steric hindrance or to the decreased diffusion in solution. The polymers also has the amide/lactam moiety in common, enabling possible hydrogen bond formation to nitrofurantoin. Conclusion: Small dendritic nitrofurantoin monohydrate crystals were achieved using amide/lactam containing polymeric as additives, whereas amide/lactam containing monomers didn't resulted in morphological changes.

Introduction: Biomacromolecules have received increased focus in the pharmaceutical field during recent years. In order to overcome their low stability, these molecules are commonly freeze-dried along with stabilizers and bulking agents. The solid form of the common bulking agent mannitol has been reported to affect the stability of freeze-dried samples. As processing conditions affect the solid form of mannitol, the effect of changing freeze drying parameters was investigated, applying in-situ freeze-drying. Materials and Mthods: In-situ freeze-drying was carried out in the temperature stage of a variable temperature X-ray powder diffractometer, connected to a vacuum pump. 100 μl of sample solution containing mannitol along with protein or the stabilizer sucrose was placed in the sample holder. The samples were frozen at different rates and dried applying vacuum to the temperature chamber, continuously recording diffractograms during the process. Results and Discussion: Freezing and annealing had the most pronounced effect on mannitol solid state during the freeze-drying process. Intermediate freezing rates caused formation of hemi-hydrate, while fast and slow freezing caused no mannitol crystallization. Formation of d-mannitol during subsequent annealing was found not to be a conversion of hemi-hydrate but rather a crystallization process from amorphous mannitol. Generally no change in mannitol solid state was seen during primary drying. Secondary drying lead to conversion of mannitol hemi-hydrate to d-mannitol. Preforming secondary drying at 30°C had little effect on the hemi-hydrate, while drying at 40°C for three hours lead to almost complete conversion of hemi-hydrate. Conclusion: In-situ freeze-drying was successfully used to provide insight into the solid state behavior of mannitol during the different stages of freeze-drying.

Purpose: This work aims at using atomic pairwise distribution functions (PDF) to analyze residual long range order in amorphous samples prepared using different preparation methods. Methods: Amlodipine besilate (AMB) was used as a model active pharmaceutical ingredient (API). The anhydrate form of AMB was used as received. The hydrate AMB (HY) form was prepared by recrystallization in water. Amorphous AMB (AM) forms were prepared by the following methods: dehydration of HY and milling of HY. The products were analyzed using X-ray powder diffraction (XRPD) and Raman spectroscopy. XRPD data were subjected to PDF analysis using Fourier transformation thereby obtaining residual long range order information. Multivariate data analysis using principal component analysis (PCA) was utilized to interpret the outcome of the PDF analysis. Results: Two different forms of AM were obtained. The amorphousness was verified by a halo present in the XRPD diffractograms. XRPD and Raman data were the same for all AM samples. The PDF analysis did however provide a route for differentiation between the different AM samples. These differences in the PDF analysis were observed for the residual long range order. The diminishing of the long range order was found as follows: milled HY>dehydrated HY. Using PCA on the PDF data samples prepared by the two different methods were seen to group differently. This was most likely caused by the presence of residual long range order of the milled samples. Conclusion: It is shown that there is a difference between the AM samples prepared by milling and dehydration. These differences were not detectable with Raman or XRPD. However, PDF analysis provided a possibility to discriminate between these two preparational routes. PDF analysis may therefore be utilized to obtain a deeper understanding of the amorphous state.