Kuentz, Martin
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Kuentz, Martin
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- PublikationOpportunities for Successful Stabilization of Poor Glass-Forming Drugs: A Stability-Based Comparison of Mesoporous Silica Versus Hot Melt Extrusion Technologies(Elsevier, 04.11.2019) Ditzinger, Felix; Price, Daniel J.; Nair, Anita; Becker-Baldus, Johanna; Glaubitz, Clemens; Dressman, Jennifer; Saal, Christoph; Kuentz, Martin [in: Pharmaceutics]Amorphous formulation technologies to improve oral absorption of poorly soluble active pharmaceutical ingredients (APIs) have become increasingly prevalent. Currently, polymer-based amorphous formulations manufactured by spray drying, hot melt extrusion (HME), or co-precipitation are most common. However, these technologies have challenges in terms of the successful stabilization of poor glass former compounds in the amorphous form. An alternative approach is mesoporous silica, which stabilizes APIs in non-crystalline form via molecular adsorption inside nano-scale pores. In line with these considerations, two poor glass formers, haloperidol and carbamazepine, were formulated as polymer-based solid dispersion via HME and with mesoporous silica, and their stability was compared under accelerated conditions. Changes were monitored over three months with respect to solid-state form and dissolution. The results were supported by solid-state nuclear magnetic resonance spectroscopy (SS-NMR) and scanning electron microscopy (SEM). It was demonstrated that mesoporous silica was more successful than HME in the stabilization of the selected poor glass formers. While both drugs remained non-crystalline during the study using mesoporous silica, polymer-based HME formulations showed recrystallization after one week. Thus, mesoporous silica represents an attractive technology to extend the formulation toolbox to poorly soluble poor glass formers.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationLipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches | a PEARRL review(Wiley, 04/2019) Ditzinger, Felix; Price, Daniel J.; Ilie, Alexandra Roxana; Koehl, Niklas; Jankovic, Sandra; Tsakiridou, Georgia; Aleandri, Simone; Kalantzi, Lida; Holm, Rene; Nair, Anita; Saal, Christoph; Griffin, Brendan; Kuentz, Martin [in: Journal of Pharmacy and Pharmacology]01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationPolyelectrolytes in Hot Melt Extrusion: A Combined Solvent-Based and Interacting Additive Technique for Solid Dispersions(Elsevier, 2019) Ditzinger, Felix; Dejoie, Catherine; Sisak Jung, Dubravka; Kuentz, Martin [in: Pharmaceutics]Solid dispersions are important supersaturating formulations to orally deliver poorly water-soluble drugs. A most important process technique is hot melt extrusion but process requirements limit the choice of suitable polymers. One way around this limitation is to synthesize new polymers. However, their disadvantage is that they require toxicological qualification and present regulatory hurdles for their market authorization. Therefore, this study follows an alternative approach, where new polymeric matrices are created by combining a known polymer, small molecular additives, and an initial solvent-based process step. The polyelectrolyte, carboxymethylcellulose sodium (NaCMC), was tested in combination with different additives such as amino acids, meglumine, trometamol, and urea. It was possible to obtain a new polyelectrolyte matrix that was viable for manufacturing by hot melt extrusion. The amount of additives had to be carefully tuned to obtain an amorphous polymer matrix. This was achieved by probing the matrix using several analytical techniques, such as Fourier transform infrared spectroscopy, differential scanning calorimetry, hot stage microscopy, and X-ray powder diffraction. Next, the obtained matrices had to be examined to ensure the homogeneous distribution of the components and the possible residual crystallinity. As this analysis requires probing a sample on several points and relies on high quality data, X-ray diffraction and starring techniques at a synchrotron source had to be used. Particularly promising with NaCMC was the addition of lysine as well as meglumine. Further research is needed to harness the novel matrix with drugs in amorphous formulations.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationBiphasic drug release testing coupled with diffusing wave spectroscopy for mechanistic understanding of solid dispersion performance(Elsevier, 2019) Jankovic, Sandra; Imanidis, Georgios; Kuentz, Martin [in: European Journal of Pharmaceutical Sciences]01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationModified Polymer Matrix in Pharmaceutical Hot Melt Extrusion by Molecular Interactions with a Carboxylic Coformer(American Chemical Society, 2019) Ditzinger, Felix; Scherer, Uta Maria; Schönenberger, Monica; Holm, Rene; Kuentz, Martin [in: Molecular Pharmaceutics]Hot melt extrusion (HME) has become an essential technology to cope with an increasing number of poorly soluble drug candidates. However, there is only a limited choice of pharmaceutical polymers for obtaining suitable amorphous solid dispersions (ASD). Considerations of miscibility, stability, and biopharmaceutical performance narrow the selection of excipients, and further technical constraints arise from needed pharmaceutical processing. The present work introduces the concept of molecularly targeted interactions of a coformer with a polymer to design a new matrix for HME. Model systems of dimethylaminoethyl methacrylate copolymer, Eudragit E (EE), and bicarboxylic acids were studied, and pronounced molecular interactions were demonstrated by 1H, 13C NMR, FTIR spectroscopy, as well as by different techniques of microscopic imaging. A difference was shown between new formulations exploiting specifically the targeted molecular interactions and a common drug−polymer formulation. More specifically, a modified matrix with Malic acid exhibited a technical extrusion advantage over polymer alone, and there was a benefit of improved physical stability revealed for the drug fenofibrate. This model compound displayed greatly enhanced dissolution kinetics from the ASD formulations. It can be concluded that harnessing molecularly designed polymer modifications by coformers has much potential in solid dispersion technology and in particular regarding HME processing.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationTowards a better understanding of solid dispersions in aqueous environment by a fluorescence quenching approach(Elsevier, 25.10.2018) Jankovic, Sandra; Kuentz, Martin; Aleandri, Simone [in: International Journal of Pharmaceutics]Solid dispersions (SDs) represent an important formulation technique to achieve supersaturation in gastro-intestinal fluids and to enhance absorption of poorly water-soluble drugs. Extensive research was leading to a rather good understanding of SDs in the dry state, whereas the complex interactions in aqueous medium are still challenging to analyze. This paper introduces a fluorescence quenching approach together with size-exclusion chromatography to study drug and polymer interactions that emerge from SDs release testing in aqueous colloidal phase. Celecoxib was used as a model drug as it is poorly water-soluble and also exhibits native fluorescence so that quenching experiments were enabled. Different pharmaceutical polymers were evaluated by the (modified) Stern-Volmer model, which was complemented by further bulk analytics. Drug accessibility by the quencher and its affinity to celecoxib were studied in physical mixtures as well as with in SDs. The obtained differences enabled important molecular insights into the different formulations. Knowledge of relevant drug-polymer interactions and the amount of drug embedded into polymer aggregates in the aqueous phase is of high relevance for understanding of SD performance. The novel fluorescence quenching approach is highly promising for future research and it can provide guidance in early formulation development.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationLipophilicity and hydrophobicity considerations in bio‐enabling oral formulations approaches – a PEARRL review(Wiley, 08/2018) Ditzinger, Felix; Price, Daniel; Ilie, Alexandra Roxana; Koehl, Niklas; Jankovic, Sandra; Tsakiridou, Georgia; Aleandri, Simone; Kalantzi, Lida; Holm, Rene; Nair, Anita; Saal, Christoph; Griffin, Brendan; Kuentz, Martin [in: Journal of Pharmacy and Pharmacology]Objectives This review highlights aspects of drug hydrophobicity and lipophilicity as determinants of different oral formulation approaches with specific focus on enabling formulation technologies. An overview is provided on appropriate formulation selection by focussing on the physicochemical properties of the drug. Key findings Crystal lattice energy and the octanol–water partitioning behaviour of a poorly soluble drug are conventionally viewed as characteristics of hydrophobicity and lipophilicity, which matter particularly for any dissolution process during manufacturing and regarding drug release in the gastrointestinal tract. Different oral formulation strategies are discussed in the present review, including lipid‐based delivery, amorphous solid dispersions, mesoporous silica, nanosuspensions and cyclodextrin formulations. Summary Current literature suggests that selection of formulation approaches in pharmaceutics is still highly dependent on the availability of technological expertise in a company or research group. Encouraging is that, recent advancements point to more structured and scientifically based development approaches. More research is still needed to better link physicochemical drug properties to pharmaceutical formulation design.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationApplication of the solubility parameter concept to assist with oral delivery of poorly water-soluble drugs – a PEARRL review(Wiley, 07/2018) Jankovic, Sandra; Tsakiridou, Georgia; Ditzinger, Felix; Koehl, Niklas; Price, Daniel; Ilie, Alexandra Roxana; Kalantzi, Lida; Kimpe, Kristof; Holm, Rene; Nair, Anita; Griffin, Brendan; Saal, Christoph; Kuentz, Martin [in: Journal of Pharmacy and Pharmacology]Objectives Solubility parameters have been used for decades in various scientific fields including pharmaceutics. It is, however, still a field of active research both on a conceptual and experimental level. This work addresses the need to review solubility parameter applications in pharmaceutics of poorly water‐soluble drugs. Key findings An overview of the different experimental and calculation methods to determine solubility parameters is provided, which covers from classical to modern approaches. In the pharmaceutical field, solubility parameters are primarily used to guide organic solvent selection, cocrystals and salt screening, lipid‐based delivery, solid dispersions and nano‐ or microparticulate drug delivery systems. Solubility parameters have been applied for a quantitative assessment of mixtures, or they are simply used to rank excipients for a given drug. Summary In particular, partial solubility parameters hold great promise for aiding the development of poorly soluble drug delivery systems. This is particularly true in early‐stage development, where compound availability and resources are limited. The experimental determination of solubility parameters has its merits despite being rather labour‐intensive because further data can be used to continuously improve in silico predictions. Such improvements will ensure that solubility parameters will also in future guide scientists in finding suitable drug formulations.01A - Beitrag in wissenschaftlicher Zeitschrift