@phdthesis{Terveer2017,
  author    = {Terveer, Nils},
  title     = {Springs and Parachutes - Development and Characterization of Novel Formulations for Poorly Water-Soluble Drugs},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154311},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2017},
  abstract  = {Successful formulation development of novel, particularly organic APIs of low molecular weight as candidates for ground-breaking pharmaceutical products is a major challenge for the pharmaceutical industry because of the poor aqueous solubility of most of these compounds. The hit identification strategies of drug development in use today apply high throughput screening techniques for the investigation of thousands of substances. This approach led to a systematical increase in molecular weight and lipophilicity and a decrease of water solubility of lead compounds reaching market access. The high lipophilicity causes an excellent permeability of the compounds which favours the absorption process from the small intestine, but it causes a decrease of water-solubility. It becomes evident that an adequate aqueous solubility is necessary for absorption of the API from the gastrointestinal fluids into the systemic circulation and hence for efficacy of the pharmaceutical product. Only an dissolved API is getting absorbed and becomes efficacious. The precipitated proportion is resigned directly. Therefore, the development of an individual formulation aligning the physicochemical characteristics is necessary for every API to produce supersaturated solutions in the small intestine and to reach an adequate bioavailability after absorption into the systemic circulation. In this thesis a specific formulation development was investigated for two exemplary poorly water-soluble APIs to replace the empirical approach often used today. The basic tyrosine-kinase inhibitor imatinib and six different acetylated amino acids were transferred into ILs. As compared to the free base and the mesylate salt, which is marketed by Novartis AG as Gleevec®, the dissolution rate as well as the supersaturation time was increased significantly. By changing the mesylate anion with its potential genotoxic risks, the total toxicity of the drug product could be decreased. The amorphous ILs proved adequate stability under forcing conditions and there was no recrystallization of the free base observed. The amorphous character of the ILs caused an increased amount of water vapour sorption which can be compensated by special packaging materials. Taken together, the presentation of imatinib as an IL is intended for oral administration as a tablet and can cause a reduction of dose because of the increased solubility. Therefore, the occurrence of side effects can be reduced as compared to Gleevec®. If there is actually an increased bioavailability to observe, has to be proved by the execution of animal trials. The novel NOX inhibitor VAS3947 is intended for the treatment of endothelial dysfunctions causing diseases like heart failure and stroke. The compounds poor aqueous solubility hindered further clinical development so far and make the drug candidate to remain in a very early stage of the drug development process. Therefore, different formulation concepts were evaluated in this study: An amorphous solid dispersion prepared from VAS3947 and Eudragit® L100 by means of spray drying was able to increase the dissolution rate and solubility of the compound significantly, but with the accomplished kinetic solubility being in the low µM range it is not possible to reach therapeutic plasma concentrations. In contrast, the incorporation into cyclodextrins resulted in an 760-fold increased solubility. Different cyclodextrins were evaluated. Especially the lipophilic derivatives of the β-cyclodextrin showed to be the most adequate excipients. The incorporation of the API into the cyclodextrin cavity was proved by means of NMR spectroscopy. Additionally, a formulation of VAS3947 and hydroxypropyl-β-cyclodextrin was prepared. This formulation is intended for the intravenous application during animal trials, which have to be conducted to get to know the pharmacokinetics of VAS3947. This formulation reached a concentration of 1 mg/mL spending striking protection of VAS3947 against degradation. Presentation of VAS3947 as a microemulsion system led also to increase the aqueous solubility of the compound, but not in the same extent as the cyclodextrin formulation. Beside the formulation development a physicochemical characterization was performed to get to know important parameters such as log P and pKa values of VAS3947. An HPLC method was developed and validated to analyse the extent of solubility improvement. A major issue of the compound VAS3947 and all related triazolopyrimidine derivatives, developed by Vasopharm GmbH, is the insufficient chemical stability because of presence of a hemiaminal moiety in the chemical structure. Stability investigations and an extensive biopharmaceutical characterization confirm the hindering of further clinical development by insufficient drug stability and high cytotoxicity. Poor aqueous solubility is an additional disadvantage which can be handled by a concerted formulation development.},
  language  = {en}
}
@phdthesis{Balk2015,
  author    = {Balk, Anja},
  title     = {Ionic liquids of active pharmaceutical ingredients: A novel platform addressing solubility challenges of poorly water soluble drugs},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121925},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2015},
  abstract  = {Starting in the late 1990s ionic liquids (ILs) gained momentum both in academia as well as industry. ILs are defined as organic salts with a melting point below 100 °C. Active pharmaceutical ingredients (APIs) may be transferred into ILs by creating salts with a bulky counterion with a soft electron density. ILs have demonstrated the potential to tune important pharmaceutical features such as the solubility and the dissolution rate, particularly addressing the challenge of poor water soluble drugs (PWSD). Due to the tunability of ILs, modification of physico-chemical properties of APIs may be envisioned without any modifications of the chemical structure. In the first chapter the potential as well as the limitation of ILs are discussed. The chapter commences with an overview of preparation and characterization of API-ILs. Moreover, examples for pharmaceutical parameters are presented which may be affected by IL formation, including the dissolution rate, kinetic solubility or hygroscopicity as well as biopharmaceutical performance and toxicology. The impact of IL formation on those pharmaceutically relevant features is highlighted, resulting in a blueprint for a novel formulation concept to overcome PWSD challenges without the need for structural changes of the API. Within the second chapter the IL concept is detailed for one specific API - counterion combination. A poorly water soluble acidic API against migraine attacks was transformed into an IL in an effort to minimize the time to maximum plasma concentration (tmax) and optimize the overall bioavailability. These studies were conducted in parallel to a prodrug of the API for comparison of the IL strategy versus a strategy involving modification of the API's structure. A significantly longer duration of API supersaturation and a 700 fold faster dissolution rate of the IL in comparison to the free acid were obtained and the underlying mechanism was elucidated. The transepithelial absorption was determined using Caco-2 cell layers. For the IL about 3 times more substance was transported in comparison to the prodrug when substances were applied as suspensions, despite the higher permeability of the prodrug, as increased solubility of the IL exceeded this effect. Cytotoxicity of the counterion was assessed in hepatic, renal and macrophage cell lines, respectively, and IC50 values were in the upper µM / lower mM range. The outcome of the study suggested the IL approach instrumental for tuning biopharmaceutical properties, without structural changes of the API as required for preparation of prodrugs. Thus the toolbox for formulation strategies of poorly water soluble drugs could be extended by an efficient concept. The third chapter focuses on the effect of different counterions on the physico-chemical properties of an API-IL, in particular to overcome the challenge of poor water solubility. Therefore, the same poorly water soluble acidic API against migraine attacks mentioned above was combined with 36 counterions resulting in ILs and low lattice enthalpy salts (LLES). Depending on the counterions, different dissolution rates, durations of supersaturation and hygroscopicities were obtained and release profiles could be tailored from immediate to sustained release. Besides, in vitro the cytotoxicity of the counterions was assessed in three cell lines. Using molecular descriptors such as the number of hydrophobic atoms, the graph theoretical diameter and the number of positive charges of the counterion, the dissolution rate, supersaturation and hygroscopicity as well as the cytotoxicity of counterions could be adequately modeled, rendering it possible to predict properties of new LLESs. Within the forth chapter different poorly water soluble APIs were combined with the counterion tetrabutylphosphonium (TBP) studying the impact on the pharmaceutical and physical properties of the APIs. TBP-ILs and low lattice enthalpy salts were prepared of the acidic APIs Diclofenac, Ibuprofen, Ketoprofen, Naproxen, Sulfadiazine, Sulfamethoxazole and Tolbutamide. NMR and IR spectroscopy, DSC, XRPD, DVS and dissolution rate measurements, release profiles and saturation concentration measurements were used to characterize the free acids and TBP salts as compared to the corresponding sodium salts. The TBP salts as compared to the free acids displayed lower melting points and glass transition temperatures and up to 1000 times higher dissolution rates. The increase in the dissolution rate directly correlated with the salts' hygroscopicity, an aspect which is critically discussed in terms of pharmaceutical translation challenges. In summary TBP ILs of solid salts were proved instrumental to approach the challenge of poor water solubility. The outcome profiled tailor-made counterions as a powerful formulation strategy to address poor water solubility, hence bioavailability and ultimately therapeutic potential of challenging APIs. In summary, a plethora of ILs and LLESs were prepared by combination of different acidic APIs and counterions. The IL and LLESs concept was compared to conventional salt and prodrug strategies. By choice of the counterion, biopharmaceutical relevant parameters were deliberately modified and release profiles were tuned ranging from immediate to prolonged release. The impact of distinct structural counterion features controlling the dissolution, supersaturation, hygroscopicity and counterion cytotoxicity were identified, correlations were presented and predictive models were built. ILs and LLESs could be proven to be a powerful concept for the formulation of poorly water soluble acidic APIs.},
  subject      = {Arzneimittel},
  language  = {en}
}