Christoph Saal

Detection of trace crystallinity in an amorphous system using Raman microscopy and chemometric analysis

A novel analytical method to detect and characterize active pharmaceutical ingredient (API) trace crystallinity in an amorphous system using Raman microscopy and chemometric methods, namely band-target entropy minimization (BTEM) and target transformation factor analysis (TTFA) is developed. The method starts with Raman mapping measurements performed on some random areas of the amorphous system. This is followed by chemometric data analysis. In the case of a system without any a priori information, the BTEM algorithm is used to recover a set of pure component Raman spectral estimates followed by component and/or crystal structure identification. In the case of a system with some a priori information, TTFA is used to predict the presence or existence of a suspected component and/or crystal structure in the observed system. Four different amorphous systems were used as models. It is demonstrated that combined Raman microscopy and chemometric methods (BTEM or TTFA) outperformed powder X-ray diffraction (PXRD) in detecting trace crystallinity in amorphous systems. The spatial distributions of drug and polymer can also be directly obtained in order to study the homogeneity of the APIs in the solid dispersions. The present methodology appears very general and applicable to many other types of systems.

Pharmaceutical salts: A summary on doses of salt formers from the Orange Book

Over half of the active pharmaceutical ingredients currently approved within the US are pharmaceutical salts. Selection of suitable pharmaceutical salts is carried out during late research or early development phase. Therefore several properties of different pharmaceutical salts of a new chemical entity are assessed during salt screening and salt selection. This typically includes physico-chemical behavior, dissolution rate and pharmacokinetics of a pharmaceutical salt. Beyond these properties also toxicological aspects have to be taken into account. As a starting point for a toxicological assessment we present an overview of the usage of pharmaceutical salts as described in the FDAs Orange Book including maximum daily doses for the most important administration routes.

Optimizing solubility: kinetic versus thermodynamic solubility temptations and risks.

The aim of this study was to assess the usefulness of kinetic and thermodynamic solubility data in guiding medicinal chemistry during lead optimization. The solubility of 465 research compounds was measured using a kinetic and a thermodynamic solubility assay. In the thermodynamic assay, polarized-light microscopy was used to investigate whether the result referred to the crystalline or to the amorphous compound. From the comparison of kinetic and thermodynamic solubility data it was noted that kinetic solubility measurements frequently yielded results which show considerably higher solubility compared to thermodynamic solubility. This observation is ascribed to the fact that a kinetic solubility assay typically delivers results which refer to the amorphous compound. In contrast, results from thermodynamic solubility determinations more frequently refer to a crystalline phase. Accordingly, thermodynamic solubility data--especially when used together with an assessment of the solid state form--are deemed to be more useful in guiding solubility optimization for research compounds.

Investigating the effect of moisture protection on solid-state stability and dissolution of fenofibrate and ketoconazole solid dispersions using PXRD, HSDSC and Raman microscopy

Enhanced dissolution of poorly soluble active pharmaceutical ingredients (APIs) in amorphous solid dispersions often diminishes during storage due to moisture-induced re-crystallization. This study aims to investigate the influence of moisture protection on solid-state stability and dissolution profiles of melt-extruded fenofibrate (FF) and ketoconazole (KC) solid dispersions. Samples were kept in open, closed and Activ-vials® to control the moisture uptake under accelerated conditions. During 13-week storage, changes in API crystallinity were quantified using powder X-ray diffraction (PXRD) (Rietveld analysis) and high sensitivity differential scanning calorimetry (HSDSC) and compared with any change in dissolution profiles. Trace crystallinity was observed by Raman microscopy, which otherwise was undetected by PXRD and HSDSC. Results showed that while moisture protection was ineffective in preventing the re-crystallization of amorphous FF, KC remained X-ray amorphous despite 5% moisture uptake. Regardless of the degree of crystallinity increase in FF, the enhanced dissolution properties were similarly diminished. Moisture uptake above 10% in KC samples also led to re-crystallization and significant decrease in dissolution rates. In conclusion, eliminating moisture sorption may not be sufficient in ensuring the stability of solid dispersions. Analytical quantification of API crystallinity is crucial in detecting subtle increase in crystallinity that can diminish the enhanced dissolution properties of solid dispersions.

Mesoporous silica‐based dosage forms improve release characteristics of poorly soluble drugs: case example fenofibrate

Mesoporous silica‐based dosage forms offer the potential for improving the absorption of poorly soluble drugs after oral administration. In this investigation, fenofibrate was used as a model drug to study the ability of monomodal (‘PSP A’) and bimodal (‘PSP B’) porous silica to improve release by a ‘spring’ effect in in vitro biorelevant dissolution tests. Also investigated was the addition of various polymers to provide a ‘parachute’ effect, that is, to keep the drug in solution after its release.

Mesoporous silica‐based dosage forms improve bioavailability of poorly soluble drugs in pigs: case example fenofibrate

Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC‐based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs. The ability of biorelevant dissolution testing to predict the in vivo performance was also assessed.

Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations – a PEARRL review

Supersaturating formulations hold great promise for delivery of poorly soluble active pharmaceutical ingredients (APIs). To profit from supersaturating formulations, precipitation is hindered with precipitation inhibitors (PIs), maintaining drug concentrations for as long as possible. This review provides a brief overview of supersaturation and precipitation, focusing on precipitation inhibition. Trial‐and‐error PI selection will be examined alongside established PI screening techniques. Primarily, however, this review will focus on recent advances that utilise advanced analytical techniques to increase mechanistic understanding of PI action and systematic PI selection.

Selection of solid-state forms: challenges, opportunities, lessons learned and adventures from recent years.

Selection of the solid-state form of an active pharmaceutical ingredient (API) has become a crucial step during pharmaceutical research and development. This can be easily recognized from the number of publications dealing with solidstate forms, in the pharmaceutical arena, which increased steadily over the last two decades. Accordingly one might ask why this has been the case, especially since the mid1990s. For example, polymorphism is known by every student occurring with classical examples such as graphite and diamond, different polymorphs of phosphor or titanium dioxide. The fundamental statement by McCrone that ‘the number of forms known for a given compound is proportional to the time and energy spent in research on that compound’ has been made in 1965. However, even if this dilemma is known for half a century, there is still no unique and 100% safe way how to select polymorphs without risks and surprises. Surprises – such as for example disappearing polymorphs, or polymorphs that suddenly appear – have been discussed in literature. Surprises did not only come from the academic world, but also from industry, where they lead to practical challenges. The famous Ritonavir case represents just one example. Further examples from industry exist – either published or non-published – and many companies doing pharmaceutical research and development of new chemical entities will have encountered adventures with polymorphism. From this perspective, the challenge mainly is given by the fact that metastable forms might convert to the thermodynamically stable form, and this might not be controlled, or the thermodynamically stable form might not even be known. However, during the last decades, the situation became still more challenging as pharmaceutical research compounds and development candidates became less soluble. This triggered the need to develop solid-state forms with increased bioavailability, solubility and dissolution rate, in other words a development away from the thermodynamically safe ground. The principle behind this is very simple: moving up in free enthalpy will lead to higher solubility of a solid-state form. However, moving higher always bears the risk of suddenly falling down. Moreover, this has become exactly the challenge that the pharmaceutical industry is facing now for more than two decades: how to develop solid-state forms with increased free enthalpy – which by definition cannot be thermodynamically stable – but are kinetically stable, avoiding the risk of falling down and converting to thermodynamically stable solid-state forms. Salt selection, the classical tool to improve solid-sate properties, has been described a long time ago. However, even if the principles are known for a century, it can be seen that the real potential of this tool have only been brought into place during the last decades, whereas hydrochloride salts have been more or less the unique solution for salt selection until the mid-1990s, during the new millennium where diversity of salts used in new APIs increased. The reason behind is obvious: As more challenging research compounds exhibiting lower solubility have been encountered, Biopharmaceutical Classification System BCS class II compounds becoming more a standard situation, selection of chloride salts did not ‘solve’ each and any problem. Further on, one has to remember that solubility and dissolution rate are not the only challenges to tackle: Further properties such as hygroscopic behaviour, particle habit, polymorphism of the salt, chemical stability, physical stability, manufacturability, processability, use of solvents, yield from manufacturing process and others also have to be addressed at the same time. As consequence, salt selection became a very individual process, specific for each new chemical entity entering clinical development. Beyond individual assessment of salt forms for research compounds, certain principles have been discovered. For example, it was realized that sulphonate salts exhibit higher solubility compared with other salt forms in many cases, even if the bs_bs_banner

Cilengitide--exceptional pseudopolymorphism of a cyclic pentapeptide.

Cilengitide (Cil) represents a cyclic pentapeptide, cyclo-(Arg-Gly-Asp-D-Phe-N-MeVal). Existence of an anhydrate form (A1) and a tetrahydrate form Cil1(H2O)4 has been observed. Surprisingly the anhydrate form proved to be more stable in aqueous environment compared to the tetrahydrate form. Assessment of thermodynamic stability has been carried out by competitive slurry experiments as well as by investigation of thermodynamic solubility. The lower solubility of the anhydrate form A1 can be explained by the hydrogen bonding motifs within the crystal structures. The tetrahydrate form Cil1(H2O)4 represents a special manifestation of a class of non-stoichiometric water-alcohol solvates Cil1(H2O)x(alcohol)y where methanol and ethanol can substitute water molecules in the crystal lattice of the tetrahydrate form leading to the hydrate-solvate systems Cil1(H2O)x(methanol)y named S1 and Cil1(H2O)x(ethanol)y named S2 with x ⩽ 4, y ⩽ 1 and y ⩽ 2-0.5x. The non-stoichiometric water alcohol solvates exhibit a higher solubility compared to the anhydrate form but convert rapidly to the anhydrate form in aqueous environments. Accordingly, the better soluble non-stoichiometric water alcohol solvates cannot be obtained by crystallization from aqueous media. However slurries or crystallization from solvent mixtures containing methanol and ethanol represent a means to obtain the highly soluble pseudo-polymorphs S1 and S2 and to circumvent formation of the low soluble anhydrate form A1.

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches - a PEARRL review

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.