In this study, a novel core-shell structured nanocarriers for oral delivery of insulin were developed. Firstly, chitosan nanoparticles (CS-NP) was prepared by cross-linking of chitosan with triphosphate TPP as the core of the core-shell structured nanocarriers. Then lipid coating chitosan nanoparticles (LCS) and pluronic F127 modified lipid coating chitosan nanoparticles (FLCS) were prepared by co-incubation of CS-NP with EPC liposomes or pluronic F127 modified EPC liposomes, respectively. The morphologies of the nanocarriers were observed using transmission electron microscope (TEM). These nanocarriers were also characterized in terms of the stability of insulin in the nanocarriers, mucus penetrating properties, and cellular association efficiencies. Under TEM a core-shell structure could be observed in FLCS indicating CS-NP formed the core which was coated with lipids. FLCS had an average diameter of 195 nm with a zeta potential of -4.3 mV. In vitro degradation study showed that with the phospholipids layer, FLCS could protect the chitosan associated insulin from degradation by trysin and α-chymotrpsin. Cellular association study performed on Caco-2 revealed that the cell association of FLCS was around 2 folds higher than CS-NP and LCS. Compared to CS-NP and LCS, FLCS exhibited enhanced mucus penetration properties in in vitro mucus penetration study. In summay, the coronal core-shell structured nanocarriers presents a promising particles for effective oral insulin delivery by combing the effects of enhancing the stability of inulin in GI tract, improving mucus penetration perperty and facilitating cellular association.

Polyethylene oxides are widely used in formulation of extended release systems, especially matrix tablets. In this study we examined the influence of different types and concentration of polyethylene oxides as well as various manufacturing procedures on drug release rate. Tablets were prepared by (a) direct compression or (b) compression of granules obtained by fluid bed wet granulation. In both cases, tablets contained paracetamol as model substance, polymer and anhydrous lactose as a diluent. Polymers of different molecular weights were used: Polyox^® WSR N-12K (approximate molecular weight 1 000 000) and Polyox^® WSR Coagulant (approximate molecular weight 5 000 000) in concentration of 20 % and 30 %. Drug release rate was determined in the rotating paddle apparatus (phosphate buffer pH= 5,8; 50rpm; volume 900ml). Swelling behaviour of tablets (water uptake and thickness of the gel layer) was examined during eight hours. Model-dependent methods were used in evaluation of drug release and swelling behaviour of PEO tablets. Lower release rate was achieved using polyethylene oxide of higher molecular weight (Polyox^® WSR Coagulant) and higher polymer content, as was expected. Both direct compression and wet granulation were efficient in prolonging drug release. Slower drug release was obtained when wet granulation was used. The slowest, zero-order drug release was achieved with Polyox^® WSR Coagulant in concentration of 30 % and wet granulation as manufacturing procedure with about 53 % of released drug after 8 hours. Polymer content was optimized considering manufacturing process, drug release kinetics as well as extended release during 8 hours of study.

APIs can crystallise in multiple distinct forms, each with their own physical properties such as dissolution rate, crystal habit or melting point. This phenomenon, known as polymorphism, has long been recognised by pharmaceutical industry and regulatory bodies alike as playing a crucial role in the formulation of drugs marketed in crystalline form. Experimental screens for polymorphs, salt forms or co-crystals are an important instrument in determining the most suitable solid form. Especially the thermodynamic stability landscape needs to be explored thoroughly, as identification of the thermodynamically most stable form is paramount. Discovery of a more stable polymorph after a plant has been commissioned has implications for patents and for the manufacturing process--especially if the more stable polymorph is discovered by a competitor. The Achilles\' heel of experimental polymorph screens is kinetics: the route to the thermodynamically most stable form may not be accessible during the experiment, causing the most stable form to be missed completely. Theoretical polymorph screens (generally referred to as crystal structure prediction) do not suffer from kinetics and are therefore the instrument of choice to complement experimental polymorph screens in order to check if possible stable polymorphs have been overlooked. In the early days, such in silico polymorph screens were highly unreliable due to the quick and dirty nature of the methods used in evaluating the relative thermodynamic stabilities of the predicted polymorphs. The availability of relatively cheap computing power, however, has changed this completely, as demonstrated in the 2007 Crystal Structure Prediction Blind Test when the application of high-quality quantum-mechanical calculations correctly predicted the crystal structures and relative stabilities of all four target compounds. The strengths and weaknesses of in silico polymorph screens with such high-quality quantum-mechanical calculations will be demonstrated using unpublished results on the antiretroviral agent Efavirenz as an example.

The recrystallisation behaviour of amorphous indomethacin and the dissolution behaviour of different solid state forms of indomethacin have been previously studied. However, the effect of crystallites developed during storage on recrystallisation during dissolution has not yet, to the best of our knowledge, been investigated. Quench cooled amorphous indomethacin stored at 30 °C and 23% or 42% relative humidity (RH) was characterised by dissolution testing, and crystallisation during storage and dissolution testing was monitored with attenuated total reflectance infrared (ATR-IR) spectroscopy and scanning electron microscopy. Freshly prepared indomethacin recrystallized to the α-form during dissolution. Particles stored at 23% RH exhibited surface crystallisation (γ form) during storage (5 days), recrystallized to the γ form during dissolution and exhibited a dissolution profile similar to the γ polymorph. Indomethacin stored at 42% RH recrystallised to the γ form. After storage (5 days), the tablet surface crystallised during dissolution to an α-γ-mixture according to FT-ATR-IR spectroscopy. After storage for 14 days, dissolution resulted in recrystallisation mostly to the γ form. This work suggests that crystallite formation in amorphous systems during storage under different conditions influences the crystallisation behaviour of the remaining amorphous material during dissolution testing.

Poly(lactic-co-glycolic acid) (PLGA) microparticles containing the drug Celecoxib (CEL) were prepared at 10% drug loading with electrospraying using the solvents acetone (ACE) and methanol (MeOH) at molar ratios 100:0, 90:10 and 75:25 (ACE:MeOH). The particles produced were characterized using scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). Drug release from the particle samples was studied for 20h in a PBS media containing 1.5% SLS. Particles were in the size range of 2-5µm with near-spherical geometry, and with smooth or grainy surfaces for particles prepared with ACE or binary solvents respectively. The grainy morphology observed with binary solvents is explained by the poorer solubility of PLGA in MeOH resulting in early precipitation during particle formation. The particles prepared with binary solvents were smaller than those prepared with single solvent partly due to a more compact conformation of PLGA. Although all particles were prepared with 10%CEL, XPS measurements showed that the CEL concentration on the surface was between 26 and 39%. The surface CEL concentration for particles prepared with binary solvents was 38-39% while it was 26% for those prepared in ACE. This big difference indicates a phase separation between PLGA and CEL in the binary solvents. The drug release study showed diffusion driven release with over 90% of the drug content released in the 20h of measurement. The particles prepared with ACE showed a gradual release while those prepared with binary solvents showed a much quicker release. This quicker release is explained by the grainy particle morphology and surface enrichment of CEL, and these particles were also shown to disintegrate during drug dissolution. Electrosprayed PLGA/CEL microparticles prepared from single and binary solvents exhibited different size and morphology as well as surface chemistry and drug release profile demonstrating the significant effects of solvents on the characteristics of these drug microparticles.

Well established techniques for increasing the solubility of poorly water soluble APIs are available. However, formulating highly water soluble APIs into dosage forms exhibiting modified release profile is gaining interest. In this work a new application for Soluplus®, a graft copolymer, is launched. A novel approach where Soluplus® is used as a dissolution modifying agent for highly water soluble APIs is introduced. Acetaminophen (APAP) and guaifenesin (GF) were used as model water soluble APIs. 95:5 and 90:10 ratios of respective API and Soluplus® were either physically mixed (PM) together or melted together on a hot plate. Melts were investigated using DSC and XRPD and compacts were submitted to dissolution studies. In case of APAP:Soluplus® a single melting event with an onset similar to pure APAP was determined by DSC. The XRPD diffractogram of molten material exhibited an amorphous halo, however further processing caused the material to crystallize. The compacts made of ground molten materials had a similar release profile and showed a slower release compared to compacts prepared from PMs. When GF:Soluplus® melts were submitted to DSC a single melting event occurred. The onset of this event did not match with the melting event of pure GF. The XRPD diffractogram of the molten samples revealed that a new polymorphic form of GF had crystallized. GF:Soluplus® compacts made of molten material revealed faster release of GF compared to compacts made of PMs of GF:Soluplus®. Using Soluplus® as a dissolution modifying agent enables tailoring of the release of the API. In this work the release of two highly water soluble APIs was modified by two different methods. Furthermore, presence of a new polymorphic form of GF was identified.

Powder properties are critical material attributes that affect pharmaceutical powder processing and therefore the quality of the final product. During processing, powders are subjected to several physical environments requiring different behavioral properties [1-2]. Thus, characterization of powder properties using only one traditional single index methods, e.g. Carr\'s Index or flow through a funnel, is insufficient for screening of excipients and prediction of in-process performance of powders [2]. Instead a multiple approach should be applied in which powders are tested by several methods each evaluating different powder properties relevant to manufacturing. Recently, Dumarey et al. have shown how an FT4 Powder Rheometer can be a valuable tool to increase the understanding of how raw material attributes affect a roll compaction process and thus the final tablet quality [4]. The FT4 Powder Rheometer is designed to characterize powders under various conditions in ways that resemble large-scale production environments [3]. The rheometer provides a comprehensive series of methods that allow powder behavior to be characterized across a whole range of process conditions. The methods include rheological, shear, compression and permeability tests which can be performed using small bulk samples, i.e. 1, 10 or 25 ml depending on the test in question. The basis for all these methods is a bench-top rheometer with a built-in balance and a PC, a set of test vessels besides an aeration control unit used for aeration tests. In this study, eight generally used excipients, i.e. microcrystalline cellulose, lactose and mannitol from various suppliers, were tested by seven different methods provided by the FT4 Powder Rheometer. In most of the tests, several of the excipients showed a different behavior (n=3, p=0.05). Still, the most differentiating parameters were obtained by a rheological stability test and a shear cell test indicating that these two methods might detect highly important powder properties. Hence, the powder rheometer is a promising tool for assessing and understanding critical raw material attributes. Powder rheology could therefore be an important step towards implementation of Quality-by-Design into pharmaceutical powder processing. [1] Howard SA. Flow Properties of Solids. In: Swarbrick J, Boylan JC, editors. Encyclopedia of Pharmaceutical Technology. 2nd ed. New York, NY: Marcel Dekker; 2002. p. 1264-85. [2] Prescott JK, Barnum RA. On Powder Flowability. Pharmaceutical Technology 2000 Oct:60-85. [3] Freeman R. Measuring the properties of consolidated, conditioned and aerated powders - A comparative study using a powder rheometer and a rotational shear cell. Powder Technol. 2007;174:25-33. [4] Dumarey M, Wikström H, Fransson M, Sparén A, Tajarobi P, Josefson M, Trygg J. Combining experimental design and orthogonal projections to latent structures to study the influence of microcrystalline cellulose properties on roll compaction. Int J Pharm. 2011;416:110-119.