14^th International Conference and Exhibition on Pharmaceutical Formulations August 28-29, 2017 Brussels, Belgium

Gabriele Sadowski is Full Professor for Thermodynamics at TU Dortmund University. She is member of the Academy of Science and Arts North Rhine-Westphalia and of the German Academy of Engineering Sciences. She is the Chair of the German working party Thermodynamics and the German Representative in the European working party Thermodynamics and Transport Properties. She is author of about 200 scientific publications in high-reputation journals in the field of chemical, biochemical and pharmaceutical engineering. The main focus of her research is studying thermodynamic properties of complex systems with particular emphasis but not restricted to those containing biological and pharmaceutical molecules. To model the thermodynamic stability of those systems, her group developed the currently worldwide most-used thermodynamic model PC-SAFT which was published in 2001. She received numerous awards for her work, the most-prestigious one being the Gottfried Wilhelm Leibniz Award of the German Science Foundation in 2011.

High-impact pharmaceutical drugs are constantly identified by (bio)medical research, with a high potential for the treatment of severe civilization diseases. However, such drugs often exhibit a very low solubility in water (and thus in biorelevant media). As they tend to crystallize during storage or after administration, they cannot be used for the development of the future-generation pharmaceuticals. Therefore, about 80% of the promising drugs currently under development never make it into a medicine. Several approaches exist to increase the bioavailability of drugs. Most of them aim at formulating the drug in a less-stable but better-soluble modification which is intended to be stabilized with the help of excipients, e.g. polymers. However, finding the right excipient for a given drug is quite difficult and today usually established by a “trialand- error” approach assisted by expensive high-throughput screening techniques. This results in tremendous costs for the development of advanced formulations and – when no appropriate formulation is found - even prevents a huge number of very promising drugs from being applied in a medicine at all. As pharmaceutical formulations usually have to be stored between manufacturing and use, it has moreover to be guaranteed, that their properties do not change during this period. This is best ensured when they are thermodynamically stable, i.e. at drug concentrations being lower than the drug solubility in the formulation. The latter is to a great extend influenced by the kind of drug and excipients, by temperature, and by relative humidity. It will be shown that the influence of humidity on the drug solubility in ASDs as well as on their kinetic stability can be predicted using thermodynamic models (1-3, 5). This provides the information whether an ASD will crystallize (destabilize) at humid conditions or not. However, the investigation of crystallization kinetics is usually performed by timeconsuming long-term experiments with recurring investigations of crystallinity, e.g. by X-ray diffraction. In this work it will therefore also be demonstrated that the kinetics of drug crystallization in ASDs can be determined only based on simple water-sorption measurements combined with a state-of-the-art thermodynamic modeling of the drug solubility in polymers at humid conditions. The latter allows accounting for the mutual influence of water sorption and drug crystallization in the ASD and thus for simultaneously predicting the amount of absorbed water and crystallized drug. Knowing the experimental water sorption as function of time thus directly provides the ASD crystallinity without the need of additional X-ray measurements.

Nagatoshi Nishiwaki received his PhD from Osaka University in 1991. He worked at Osaka Kyoiku University (1991–2008). From 2000 to 2001, he joined Karl Anker

Jørgensen’s group at Aarhus University, Denmark. Between 2008 and 2009, he worked at Anan National College of Technology. He then moved to the School of

Environmental Science and Engineering, Kochi University of Technology, in 2009, and he became a Professor in 2011. His research interests comprise synthetic

organic chemistry using nitro compounds, heterocycles (ring transformations, 1,3-dipolar cycloadditions etc.), and pseudo- intramolecular reactions. He has more

than 120 papers and 20 review articles.

Dinitropyridone 1 is an excellent substrate for the nucleophilic type ring transformation to afford heterocyclic compounds

and nitroanilines those are not easily available by alternative methods. When pyridone 1 was reacted with aromatic ketone

in the presence of NH4OAc, 6-arylated 3-nitropyriines 2 were formed besides bicyclic compounds 3. This method was also

applicable to synthesis of cycloalka[b]pyridines 4 and 6-alkynylated/alkenylated pyridines 5, respectively. It was found to be

possible to use aldehydes as the substrate, which leading to 3,5-disubstituted pyridines 6. On the other hand, when aliphatic

ketones were employed as the substrate, two kinds of ring transformation proceeded. Namely, 2,6-disubstituted 4-nitroanilines

8 were formed in addition to nitropyridines 7. It was successful to apply this protocol to synthesis of N,N,2,6-tetrasubstituted

nitroanilines 9 upon treatment of dinitropyridone 1 with ketone and amine in the presence of acetic acid.

Christian Luebbert graduated in Chemical Engineering at TU Dortmund University, Germany in 2014. During his work as Research Assistant at the Laboratory of

Thermodynamics, he focuses on the physical long-term stability of amorphous pharmaceutical formulations. With his expertise, he contributes from an engineering

point of view to pharmaceutically highly relevant development of formulation strategies for poorly water-soluble drugs.

Numerous recently-developed Active Pharmaceutical Ingredients (APIs) have a low solubility in water leading to

insufficient absorption and bioavailability. To overcome this solubility limitation, APIs are molecularly dispersed in

hydrophilic polymers. The resulting formulations are denoted as Amorphous Solid Dispersion (ASDs). For the administration

of new pharmaceutical formulations, long-term stability tests are imposed by regulatory authorities at defined conditions

of temperature and humidity (25°C, 60% relative humidity (RH) for 12 months tests and 40°C, 75% RH for accelerated sixmonths

tests). Recrystallization of the amorphous API and/or moisture-induced amorphous-amorphous phase separation

(miAPS) might occur during storage indicating the thermodynamic instability of the ASDs. Long-term stable formulations

are nowadays identified by trial-and-error principles. The aim of this work was to a-priory estimate the long-term stability

of ASDs by applying advanced thermodynamic methods1 and thus to reduce the experimental effort for finding promising

polymeric carriers suitable for formulation development. In order to validate the thermodynamic predictions, ASDs with

different API/polymer compositions were prepared and subjected to two years enduring long-term stability tests at the

aforementioned conditions. Recurring PXRD measurements were performed to detect recrystallization and Raman mapping

was applied to quantify miAPS. Water sorption was observed as function of time using a magnetic suspension balance. Water

sorption and thereby induced phase transitions (recrystallization/ miAPS) could be predicted in quantitative agreement with

the experimental data. This study showed that results of long-term stability tests can be predicted correctly in early stages of

drug development and that promising polymer candidates for long-term stable ASDs can be identified prior to long-term

stability tests by thermodynamic modeling.

Shrawan Baghel is currently doing PhD in “Novel technologies and optimized formulations for delivery of solid dispersion of BCS class II drugs” at Pharmaceutical

and Molecular Biotechnology Research Center (PMBRC), Waterford Institute of Technology. He is the winner of Science Foundation Ireland scholarship for this

project in collaboration with Synthesis and Solid State Pharmaceutical Centre. The main aim of this project is to gain an insight into the mechanistic and molecular

aspects of solid dispersion prepared by spray drying, hot melt extrusion and supercritical fluid process using DSC, XRD and NMR. He had also planned, conducted,

interpreted nanotechnology and lipid based formulation approaches to increase the solubility and dissolution of poorly soluble drugs.

Amorphous Solid Dispersions (ASDs) are of great interest as enabling formulations because of their ability to increase

the bioavailability of poorly soluble drugs. However, the dissolution of these ASD based formulations results in highly

supersaturated drug solution that can undergo different types of phase transition. We have investigated the dissolution

performance of amorphous solid dispersions of poorly water-soluble dipyridamole (DPM) and cinnarizine (CNZ) spraydried

amorphous solid dispersions (ASDs) using polyvinyl pyrrolidone (PVP) and polyacrylic acid (PAA) as a carrier matrix.

Dissolution studies were carried out under non sink conditions and solution phase drug-polymer interactions was characterized

using proton NMR. It was found that the dissolution of ASDs led to sustained supersaturation, the duration of which varied

depending on the drug loading and type of polymer used in the formulation. The main mechanism for drug supersaturation

generation and prolongation was found to be anti-plasticization effect of polymers on amorphous drugs within spray dried

ASDs and the ability of polymers to reduce the crystal growth rates of DPM and CNZ. To further understand the molecular

mechanism behind supersaturation stabilization in the presence of polymer, we employed, Solution 1H NMR. The change

in electron densities of proton and the relative intensities of peak shifts indicated the nature of interaction between drug and

polymer in different systems are different. These different effects suggest that DPM and CNZ interacts in a different way with

PVP and PAA in solution which goes some way towards explaining the different polymeric effect, particularly in terms of

inhibition of drug recrystallization and dissolution of DPM and CNZ ASDs. . The overall supersaturation profile observed thus

depended on a complex interplay between dissolution rate, polymer type, drug loading, crystallization mechanism of drugs

and drug-polymer interaction in the solution state.

Shahnaz Usman has received her PhD in Pharmaceutics from University of Karachi during the period of 2007. Currently, she is working as an Associate Professor

in Department of Pharmaceutics in RAK College of Pharmaceutical Sciences. She is appointed as Reviewer by different international journals. She is a registered

member of Pakistan Pharmacist Association.

Objective: The aim of the present study was to prepare ODT by using relatively a simple direct compression technique with

high mechanical strength while keeping the attributes of fast disintegration and dissolution to improve the bioavailability of

the drug.

Method: Mannitol and microcrystalline cellulose were studied as diluents in the same quantity for manufacture of montelukast

sodium tablet using crospovidone as super disintegrants and sodium bicarbonate as wicking agent. The blend was examined

for angle of repose, bulk and tapped density, compressibility index, and Hausner’s ratio. The drug-excipients interaction was

investigated by FTIR. After compression hardness, friability, disintegration and dissolution, all the formulations batches were

analyzed.

Results: It was found that microcrystalline cellulose was suitable diluent for tablets considering hardness, friability and

disintegration time. Ten formulations F1 to F10 were prepared by central composite methods (two level factorial designs) for

the selection of optimum concentration of disintegrants and diluents.

Conclusions: The overall results showed that crospovidone was the best super-disintegrant for showing the shortest

disintegration time while MCC was the good diluent in preparing montelukast Oro-dispersible tablet and this suggested the

possibility of utilizing the selected best formula (F2) in the preparation of Oro-dispersible tablet as a new dosage form for oral

administration.

Tomasz Urbaniak is a Pharmacist and Research Assistant in Physical Chemistry Department of Faculty of Pharmacy, Wroclaw Medical University. His activity

includes evaluation of polymerization methods, structural analysis of polymeric materials on molecular and bulk level, and examination of drug release from

nanometric and micrometric particles. Also, utilization of quantum chemistry calculations in the field of pharmaceutical science is in scope of his interests.

Interdisciplinary approach is the way he thinks and acts in his work.

Poly-E-caprolactone (PCL) is biodegradable, nontoxic polyester synthesized mainly in ring-opening polymerization

(ROP) of E-caprolactone (CL). PCL alone or in blends was utilized in numerous medical applications, such as scaffolds,

implants, nano- and micro- drug carriers. It is characterized by slow degradation of polyester chains in hydrolytic mechanism.

Lamivudine (LV), as well as other antiretroviral drugs used in HIV-1 treatment, targets infected immune system cells, mainly

CD4+ T helper cells. However, other infected cells like macrophages, monocytes, dendritic cells are found through whole body,

including lungs and central nervous system. This cells halflife, measured in weeks/years, is dramatically longer in comparison

to CD4+ T helper cells, which is counted in hours/days. Such cells are often recognized as reservoirs of retroviruses, especially

these which are found in sites hardly available for drug substances, so called “sanctuaries”. The aim of this study was to design a

process of poly-E-caprolactone-lamivudine conjugate (PCL-LV) synthesis, and forming it into microspheres. Due to extremely

slow hydrolytic degradation, phagocytosis would be main mechanism of intravenously administered particles clearance.

Suggested mechanism of ROP includes formation of bond between initiator and polymer backbone. Drug bound covalently

to oligomeric chain would not be released from polymeric matrix in to plasma, therefore whole administered dose would

eventually achieve phagocytic cells, i.e., HIV-1 infected macrophages, monocytes or dendritics cells. Conjugate structure was

confirmed by the proton nuclear magnetic resonance and electro-spray ionization time of flight mass spectroscopy. Further

stage of study included microsphere forming in a variant of solvent evaporation method. Shape and size of obtained particles

was determined by scanning electron microscopy, light microscopy and dynamic light scattering. Average molecular weight of

obtained polymers was 5400 Da, size of prepared particles varied from nanometric to micrometric dimensions.

Supamas Napavichayanun is a PhD student, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Thailand. She earned a BSc from Faculty of

Pharmaceutical Sciences, Chulalongkorn University in 2010. Her research experience has ranged from protein including silk proteins and biomaterials. She also

did clinical researches in the area of dermatology especially materials for wound healing application.

Sericin has been conducted to characterize its immunomodulatory effects especially anti pro-inflammatory activities for

decades. In addition, it is also well known that hyperpigmentation disorders such as post inflammatory hyperpigmentation

(PIH) and melanoma, are a major concern not only in white skin type people, but also raises in darker skin type of Asian

population. Although there are many types of therapeutic products, more effective treatments still need to be evolved. The

important modulators of epidermal innate immune responses are melanocytes and dendritic cells (DCs), which composed of

induction, regulation, and maintenance of inflammatory responses on skin. However, the immunomodulatic role of sericin

on melanocytes and DCs relate to therapeutic effect of hyperpigmentation disorders has not been well established. Moreover,

sericin composes of the anti-tyrosinase property. Although the most prominent target for inhibitors of hyperpigmentation is

tyrosinase, unfortunately, a little is known about its anti-melanogenic property and clinical efficacy. In this study, we conducted

in vitro model and electron microscopic studies (immune-gold labeling) to determine (i) the tolerogenic effect sericin on

melanocytes and DCs indicated by the level of IL-10 and transforming growth factor (TGF)-ß, (ii) the anti-melanogenic

property of sericin characterized by tumor progressive marker (Mtif) and (iii) the anti-tyrosinase effect of sericin using

tyroninase marker. The results showed that sericin (at leat 5 μg/ml) composed of tolerogenicity, anti-tyroninase and antimelanogenicity

effects on melanocytes and DCs as demonstrated by the up-regulation of IL-10 and TGF- ß in association with

the down-regulation of tyrosinase and Mtif, respectively. This study provides the understanding of immunomodulatic role of

silk sericin on melanocytes and DCs underlying hyperpigmentation disorders lead to the applications allowing affected people

to have a better quality of life and their guidelines for therapeutic approaches.

Kampanart Huanbutta has his expertise in drug delivery system and application of polymer in pharmaceutical dosage forms. He graduated from Faculty of

Pharmacy, Silpakorn University, Thailand. After that, he received Postdoctoral Scholarship from Erasmus Mundus to conduct research concerning anticancer drug

delivery system in University of Porto, Portugal. Now he is working at Faculty of Pharmaceutical Sciences, Burapha University as an Assistant Dean for academic

affair and post-graduation study. He also works as Secretary General of Pharmaceutical Association of Thailand under Royal Patronage. He has published research

and review articles in international journals for more than 20 articles.

Crude seed gum and their carboxymethyl derivatives from Cassia fistula seed was developed and characterized to apply

as the pharmaceutical disintegrant in fast disintegrating Thai cordial tablet. The chemical structure of crude gum was

chemically modified via carboxymethylation. Degree of substitution (DS) of carboxymethylated gums was determined.

Carboxymethylated gums with minimum and maximum DS values were chosen for further application. IR absorption spectra

of gum samples were observed to verify their chemical structure changes. In physical properties, the intrinsic viscosity and

swelling property of all gum samples were evaluated. The results showed that carboxymethylated gums had higher intrinsic

viscosity than those of crude gum. Moreover, they could swell and be soluble in cold water better than those of crude gums.

In conclusion, the modified gums from both plants could provide higher hardness and be better used than that crude gums

for fast disintegrating Thai cordial tablet. However, this is a preliminary assessment to expressing pharmaceutical application

possibility of these gums as disintegrants, diluents and drug release controlling agents.