Download In this work we evaluate, for the first time, two mechanical co

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Solubility of Crystalline Organic Compounds in High and
Low Molecular Weight Amorphous Matrices Above and Below
the Glass Transition by Zero Enthalpy Extrapolation
Youness Amharar, Vincent Curtin, Kieran H. Gallagher and Anne Marie Healy*
School of Pharmacy and Pharmaceutical Sciences, University of Dublin, Trinity
College, Dublin 2, Ireland.
*Corresponding Author University of Dublin, Trinity College, School of Pharmacy and
Pharmaceutical Sciences, Panoz Institute, Dublin 2, Ireland.
E-mail: [email protected]. Tel: +353 (0) 1 896 1444 Fax: +353 (0) 1 896 2810
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Keywords: Solubility, amorphous, polymer, drug, excipient, thermal analysis.
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Keywords: Solubility, amorphous, molecular dispersion, polymer, drug, excipient,
thermal analysis.
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Abstract
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Pharmaceutical applications which require knowledge of the solubility of a crystalline
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compound in an amorphous matrix are abundant in the literature. Several methods
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that allow the determination of such data have been reported, but so far have only
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been applicable to amorphous polymers above the glass transition of the resulting
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composites. The current work presents, for the first time, a reliable method for the
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determination of the solubility of crystalline pharmaceutical compounds in high and
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low molecular weight amorphous matrices at the glass transition and at room
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temperature (i.e. below the glass transition temperature), respectively.
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The solubilities of mannitol and indomethacin in polyvinyl pyrrolidone (PVP) K15 and
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PVP K25 respectively were measured at different temperatures. Mixtures of
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undissolved crystalline solute and saturated amorphous phase were obtained by
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annealing at a given temperature. The solubility at this temperature was then
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obtained by measuring the melting enthalpy of the crystalline phase, plotting it as a
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function of composition and extrapolating to zero enthalpy. This new method
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yielded results in accordance with the predictions reported in the literature.
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The method was also adapted for the measurement of the solubility of crystalline
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low molecular weight excipients in amorphous active pharmaceutical ingredients
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(APIs). The solubility of mannitol, glutaric acid and adipic acid in both indomethacin
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and sulfadimidine was experimentally determined and successfully compared with
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the difference between their respective calculated Hildebrand solubility parameters.
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As expected from the calculations, the dicarboxylic acids exhibited a high solubility in
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both amorphous indomethacin and sulfadimidine, whereas mannitol was almost
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insoluble in the same amorphous phases at room temperature.
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This work constitutes the first report of the methodology for determining an
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experimentally measured solubility for a low molecular weight crystalline solute in a
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low molecular weight amorphous matrix.
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1. Introduction
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The use of amorphous molecular dispersions for drug delivery purposes is becoming
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of greater importance in the pharmaceutical industry (Ford, 1986; Serajuddin, 1999;
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Setia and Squillante, 2003). These drug-excipient amorphous formulations are mainly
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used to improve the dissolution of poorly water soluble drugs (Hülsmann et al.,
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2000). Dispersing an active pharmaceutical ingredient (API) in an amorphous
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polymeric matrix at the molecular scale not only increases its solubility and
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dissolution rate but can also prevent its recrystallisation over time (Leuner and
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Dressman, 2000; Repka et al., 2008). Nevertheless, finding a suitable polymer and
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drug loading can be difficult. Indeed, in order to disperse a sufficient amount of API
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in the amorphous solid, the solubility of the crystalline API in the polymer must be
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sufficiently high (Marsac et al., 2009, 2006). Moreover, the drug loading should not
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exceed the solubility in order to avoid the recrystallisation of the API during the drug
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shelf-life (Qi et al., 2010), even though this unwanted phenomenon can be kinetically
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prevented in some cases (Marsac et al., 2006). Therefore solubility is a key
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parameter and its accurate assessment is crucial for the development of amorphous
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dispersion formulations.
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The determination of the solubility of a crystalline excipient in an amorphous API can
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also be of interest, as recently shown by Curtin et al. (Curtin et al., 2013a, 2013b).
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They demonstrated the ability of crystalline low glass transition temperature (Tg) low
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molecular weight excipients to prevent the amorphisation of an API upon milling by
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reducing the Tg of the resulting composite. The authors highlighted that the
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efficiency of the process, arising from the Tg lowering effect, was highly dependent
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on the solubility of the excipient in the amorphous API.
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The experimental determination of the solubility of an API in an excipient and vice
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versa is challenging. The most widespread method for the determination of the
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solubility of a crystalline compound in an amorphous polymer is known as the
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‘melting point depression’ method (or scanning method). This thermal technique,
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introduced by Tao et al., is based on the measurement of the dissolution endpoint of
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solute/polymer mixtures prepared by milling (Tao et al., 2009). The plot of the
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dissolution endpoint as a function of composition gives the solubility curve of the
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crystalline solute in the amorphous polymer. However, the solubility cannot be
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experimentally measured below Tg+30°C by this method because the high viscosity
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of polymers makes achieving equilibrium difficult (Tao et al., 2009). In order to
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circumvent this limitation and to enable the determination of solubility at
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temperatures closer to Tg, Tao et al. improved their protocol by annealing the
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solute/polymer mixtures over a long time (10h) (Sun et al., 2010). Nonetheless this
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‘annealing method’ could only be applied down to Tg+20°C and the solubility below
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this temperature could only be predicted by determining the intersection between
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the Tg curve of the composite and the extrapolation of the solubility curve (Sun et
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al., 2010). Even though this technique is efficient and convenient for the
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determination of the solubility of an API in polymer above Tg, the typical storage
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temperature of a drug is usually below Tg.
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Recently, the group of Descamps has designed a new protocol for the determination
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of the solubility of an API in a polymeric matrix (Mahieu et al., 2013). In this method,
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the saturated state is reached by demixing of supersaturated amorphous solid
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solutions and not by dissolution of crystalline drug into the amorphous polymer, as
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for the melting point depression method. According to Mahieu et al. the presence of
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a large amount of solute in the amorphous phase plasticizes the polymer (decreases
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the Tg) thus enhancing the molecular mobility and therefore speeds up the
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equilibration step. They validated this new technique against a previously described
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system, the solubility of which had been determined by Tao et al. through the
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annealing method (Sun et al., 2010). Nevertheless, as for the Tao et al. method, this
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promising new approach has only been used above the Tg so far.
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As a thermodynamic property, the drug/polymer solubility is properly defined only
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above Tg, where the amorphous phase is a supercooled liquid at equilibrium. Below
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Tg, the supercooled liquid becomes a glass which relaxes and therefore no
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thermodynamic solubility can be determined. However, since the glass relaxation is
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slow, an apparent solubility can be estimated (Qian et al., 2010). Marsac et al.
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developed a model in which they could calculate the Flory Huggins interaction
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parameter, χ, from solubility measurements of the solute in the liquid low molecular
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weight polymer analog (Marsac et al., 2006). Despite the fact that this model enables
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the calculation of the solubility at temperatures below Tg, it works under the
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assumption that the drug-polymer and drug-monomer interaction parameters are
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the same. Furthermore this method is only applicable for polymers that have liquid
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monomers. More recently, Bellantone et al. published a new method for
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determining the solubility of a drug in a solid polymer near room temperature
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(Bellantone et al., 2012). They calculated the free enthalpy variation associated with
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the formation of the amorphous solid dispersion from the unmixed polymer and
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crystalline API from thermal analysis data. They determined the drug solubility in the
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polymer by calculating the minimum of the free enthalpy change versus the
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dissolved drug concentration.
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An experimental method originally developed by Theeuwes et al. for the
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determination of the solubility in amorphous molecular dispersions above and below
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Tg seems promising (Theeuwes et al., 1974). This method is based on the principle
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that when a mixture has a drug-polymer composition above the solubility, the
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saturated amorphous solid phase is in apparent equilibrium with undissolved crystals
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of API. This fraction of unsolubilised drug will exhibit a melting endotherm upon
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differential scanning calorimetry analysis (DSC). The solubility is then obtained by
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plotting the measured melting enthalpy as a function of drug composition and
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extrapolating it to zero. This method has been extensively used to determine the
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minimum amount of polymer required to prevent API crystallization in amorphous
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dispersions prepared by spray drying (Corrigan, 1975) as well as for solubility
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purposes (Gramaglia et al., 2005; Qi et al., 2010) and has the potential to overcome
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the limitations of the other techniques.
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This paper reports the development of a fast and standard method for the
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determination of the solubility of a crystalline organic compound in an amorphous
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polymer above and at Tg combining the benefits of the annealing method of Tao et
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al. and the thermal analysis reported by Theeuwes et al. The advantage of the
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technique presented in the current work lies in the production of a saturated
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amorphous phase ensured by the annealing step and the accuracy of the zero
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enthalpy extrapolation for the determination of its composition. The aim of this work
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is to validate this protocol against other results reported in the literature and to
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extend it to low molecular weight amorphous systems.
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2. Materials and Methods
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2.1. Materials. Polyvinyl pyrrolidone (PVP) K15 (Mw ≈ 10000 g.mol-1), PVP K25 (Mw
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≈ 24000 g.mol-1), sulfadimidine (SD) (Mw = 278.33g.mol-1), adipic acid (AA) (Mw =
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146.14 g.mol-1), glutaric acid (GA) (Mw = 132.11 g.mol-1), mannitol (MN) (Mw =
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182.20 g.mol-1) and indomethacin (IM) (Mw = 357.79 g.mol-1) were purchased from
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Sigma-Aldrich, Ireland.
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2.2. Methods.
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2.2.1. Milling. Ball milling was performed with a PM 100 high energy planetary mill
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(Retsch, Germany) at room temperature, as previously described by Curtin et al.
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(Curtin et al., 2013b). 2.5 g of material were placed in stainless steel milling jars of
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50 cm3 volume with three stainless steel balls of diameter 20 mm, corresponding to a
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ball to powder mass ratio of 40:1. The speed of the solar disk was set at 400 rpm
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and the milling duration to 10 minutes.
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2.2.2. Thermal analysis. Differential scanning calorimetry (DSC) experiments were
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conducted using a DSC Q200 (TA Instruments, United Kingdom) in hermetic pans
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with 1 pinhole and sample weights were between 2 and 6 mg with a heating rate of
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20 °C min-1. Nitrogen was used as the purge gas. The instrument was calibrated for
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temperature and cell constant using high purity indium. Unless otherwise noted, the
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reported Tg is the midpoint temperature of the glass transition.
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2.2.3. Powder X-ray diffraction. Powder X-ray diffraction (pXRD) measurements
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were performed on samples placed on a low background silicon sample holder using
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a Rigaku Miniflex II desktop X-ray diffractometer (Rigaku, Tokyo, Japan). The pXRD
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patterns were recorded from 5° to 40° on the 2θ scale at a step of 0.05°.s-1. The X-
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ray tube composed of Cu anode (λCUKα = 1.54 Å), was operated under a voltage of 30
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kV and current of 15 mA.
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2.2.4. Determination of the solubility of a crystalline API in a polymer. API/polymer
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mixtures were milled using the milling conditions described above. The resulting
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powders were then annealed at a constant temperature in the DSC cell under
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nitrogen atmosphere in order to prevent chemical degradation over 10 hours. For
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samples stored at room temperature, the annealing duration was extended to 48
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hours. High API loads have been deliberately used in order to ensure the presence of
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a significant amount of crystals within the solid during the annealing (Tao et al.,
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2009). At this stage a mixture of crystalline API (the original polymorph) and
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amorphous polymer saturated with the API was obtained, which was confirmed by
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pXRD. The melting enthalpy of the resulting crystalline phase was then determined
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by DSC as described above and plotted as a function of excipient mass fraction. All
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experiments were performed at least in duplicate (n=2). HPLC was used to ensure
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the chemical integrity of the samples.
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2.2.5. Determination of the solubility of a crystalline low molecular weight
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excipient in an amorphous API. API/excipient mixtures were milled as described in
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the previous section. The resulting powders were poured on aluminium foil and
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heated up to 200°C on a heating plate under nitrogen atmosphere to allow the
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complete melting of the crystals. The aluminium foil was then removed from the
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heating plate and immediately placed at 25 °C in order to quench-cool the liquid. The
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resulting solid phases were kept at this temperature under dry atmosphere (N 2) for 2
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days. High excipient loads have been used in order to ensure the presence of a
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significant amount of crystals within the solid post-quench (Tao et al., 2009). pXRD
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was used to ensure the presence of amorphous API/excipient composite and
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undissolved crystalline excipient. The melting enthalpy of the resulting crystalline
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phase was then determined by DSC as described above and plotted as a function of
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excipient mass fraction (n=2). HPLC was used to ensure the chemical integrity of the
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samples.
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2.2.6. High performance liquid chromatography analysis (HPLC). The chemical
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integrity of IM, SD, GA, AA and MN post-processing was determined using a
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Shimadzu HPLC Class VP series with a LC-10AT VP Pump, SIL-10AD VP autosampler
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and SCL-10VP system controller.
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The mobile phase was vacuum filtered through a 0.45 µL membrane filter (Pall
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Supor-450). The mobile phases consisted of acetonitrile/0.1M acetic acid 60/40 (v/v)
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for IM (Chauhan et al., 2004), water (purified) for MN (British Pharmacopeia, 2003),
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methanol/buffer pH 6.5 20/80 (v/v) for SD and a phosphoric acid solution (pH=2.1)
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for GA and AA.
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Separation was performed on a Luna C18 (250mm length, diameter 4.6mm, particle
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size 5 µm) for IM with elution carried out isocratically and at room temperature
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(Chauhan et al., 2004). A TSK-Gel 6000PWXL (30cm length, 7.8mm diameter, pore
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size 13 µm) was used for MN with isocratic elution at a temperature of 50 °C (British
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Pharmacopeia, 2003). A Phenomenex Inertsil ODS (3) C18 column (150 mm length,
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diameter 4.6 mm, particle size 5 μm) was used at room temperature with isocratic
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elution for SD. For GA and AA a LiChrosorb RP-10 column (250 mm length, internal
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diameter 4 mm, and particle size 10 μm) was used at room temperature with
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isocratic elution.
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UV detection was used at a wavelength of 254 nm for IM, 260 nm for SD, 210 nm for
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GA and AA using a SPD-12A VP UV-Vis detector. A flow rate of 1 ml/min was used for
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IM, SD, GA and AA. Differential refractometry was used for detection of mannitol
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using a Waters 410 Differential Refractometer held at a temperature of 50 °C with a
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flow rate of 0.5 ml/min.
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Class-VP 6.10 software was used for peak evaluation.
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2.2.7. Hildebrand solubility parameter. The Hildebrand solubility (δ) parameters
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were determined utilising the Fedors group contribution method (Fedors, 1974) The
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calculation involves the summation of molar vaporization enthalpies of structural
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fragments in the material. The molecular volume can be derived from its density or
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alternatively in an additive fashion similar to that of the molar enthalpies. The
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Hildebrand solubility parameter was determined from the equation: δ=(ΔE v/Vm)1/2
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where ΔEv is the energy of vaporisation and Vm is the molar volume.
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2.2.8. Nomenclature. The term matrix denotes the solid phase in which the solute is
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dissolved. It can be either polymeric or not, depending on the system studied.
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The system formed by a mixture of the amorphous matrix A and the crystalline
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solute B is denoted AB. If this mixture contains X % w/w of B, the resulting solid is
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denoted ABX. For example, PVPK15MN90 stands for a composite formed between
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PVPK15 and 90% w/w of MN.
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As explained in the introduction, below the glass transition temperature, amorphous
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solids cannot be thermodynamically defined. Therefore, terms such as ‘solubility’ or
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‘equilibrium’ cannot be used to describe those systems. However, they will be used
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instead of ‘apparent solubility’ and ‘apparent equilibrium’ respectively for clarity.
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3. Results and Discussion
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3.1
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Tao et al. have demonstrated that co-milling the API and the polymer together can
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improve the mixing between the components by reducing their particle size.
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Moreover it can speed up the homogenisation of the dispersion by inducing
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complete or partial dissolution of the solute in the polymer (Mahieu et al., 2013; Tao
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et al., 2009). On the other hand, a long milling step can result in partial
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amorphisation of the API especially in the case of IM which is known to readily
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amorphise upon milling (Planins et al., 2010). A milling time of 10 minutes was
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therefore chosen for all the systems. These conditions did not induce the
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amorphisation of MN, as determined by DSC. Furthermore the limited amount of
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amorphous IM produced by milling was shown to recrystallise during the annealing
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step above 60°C (Planins et al., 2010). As a result, the powder obtained after milling
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and subsequent annealing was considered as a biphasic system composed of a
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saturated amorphous molecular dispersion in equilibrium with the undissolved
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excess of crystalline API.
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Figure 1 shows the DSC curves of the PVPK15MN system for various compositions
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annealed at 105°C. An endothermic event corresponding to a melting is present on
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each thermogram showing the presence of crystalline MN after annealing. It can
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Solubility of an API in a polymeric matrix above and near the Tg.
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therefore be assumed that the solubility at this temperature is lower than 60%. The
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thermograms show a slight shift of the melting peak as a function of MN
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composition. The annealed materials were analysed by pXRD (data not shown) in
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order to assess the nature of the solid phases remaining after the thermal treatment.
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These analyses showed that the only crystalline phase that remained in equilibrium
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with the amorphous composite after annealing was the original β polymorph of MN.
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The Tg of the amorphous phase could not be detected owing to the small quantity of
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PVPK15 compared to the large amount of crystalline MN, but should be lower than
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105°C according to Tao et al. (Sun et al., 2010; Tao et al., 2009).
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The plot of the heat of melting of MN for each composite and at various
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temperatures is shown in Figure 2. A linear relationship between the MN mass
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fraction and the melting enthalpy is observed with a good correlation (R2>0.99). For
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a given composition, the amount of crystalline MN remaining after annealing
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increases when the temperature decreases, indicating an increase in the solubility of
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MN with temperature. The solubility of MN in amorphous PVPK15 was then
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estimated as the zero enthalpy interception point by extrapolation. The solubility
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values obtained by this method are: 13.2%, 14.3%, 17.3% and 23.2% at 97°C, 105°C,
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117°C and 137°C respectively.
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The solubility of IM in PVPK25 at 110°C and 120°C (which are temperatures above
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the Tg according to Tao et al. (Sun et al., 2010; Tao et al., 2009)) was determined
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using the same protocol as described above. The presence of the starting γ
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polymorph of IM was assessed by pXRD. The thermograms of PVPK25IM mixtures
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show a shift of the melting peak as a function of IM composition (Figure 3). Such
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shifts are usually observed at low heating rates for systems exhibiting a high
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solubility of the API in the polymer (Marsac et al., 2009). In the case of PVPK25IM the
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melting point shift is visible even at a high heating rate, which is a sign of high
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solubility in PVPK25. As for the PVPK15MN system, the plot of the heat of fusion
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against IM mass fraction shows linearity (R2>0.99) both at 110°C and 120°C as
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depicted in Figure 4. The solubilities obtained by extrapolation are significantly
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higher than those of MN in PVPK15: 61.5% and 66.6% at 110°C and 120°C
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respectively.
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Tao et al. determined the temperature at which the dissolution is complete for a
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given solute/polymer composition by using the scanning method. This slow
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dissolution takes place during the DSC scan and requires good kinetic conditions (low
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polymer viscosity, high dissolution rate). For this reason the scanning method is not
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adequate for the determination of dissolution endpoints near Tg where the high
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polymer viscosity hinders the dissolution of the solute. On the other hand in the
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annealing method, a mixture solute/polymer is annealed at a given temperature and
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subsequently analysed by DSC to search for a residual dissolution endotherm. The
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absence or presence of a thermal event then indicates that the annealing
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temperature is higher or lower than the solubility temperature respectively. The
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upper and lower bounds of the solubility are therefore determined by systematically
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varying the annealing temperature. Tao et al. have measured the solubility of MN in
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PVPK15 between 165°C and 130°C by the scanning method (Tao et al., 2009). They
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have also measured the solubility of MN in PVPK15 and IM in PVPK25 between 165°C
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and 120°C and 160°C and 110°C respectively by the annealing method (Sun et al.,
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2010). The resulting solubility curves are presented in Figure 5. As predicted by the
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zero enthalpy extrapolation method, the solubility of the IM in PVPK25 system is
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significantly higher than that of MN in PVPK15. The solubility values determined in
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this paper are in good agreement with those reported by Tao et al.
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Despite the difficulty of using the melting point depression near the glass transition,
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the solubility can be estimated by extrapolating the curve down to Tg. Tao et al.
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could therefore predict that the solubility of crystalline MN (β polymorph) in PVPK15
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is 13% at 105°C and 11% at 97°C. According to their extrapolation, at 97°C, the
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saturated solution exists at the glass transition temperature. These results are in
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good agreement with those determined by the zero enthalpy extrapolation method
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(Table 1 and Figure 5). The validation of the results at Tg presented in this paper
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shows that a long annealing step is sufficient to circumvent the kinetic problems
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encountered near the glass transition by the scanning method. Therefore, both the
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zero enthalpy extrapolation and Tao’s annealing method are promising for the
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determination of solid/solid solubilities above and below Tg.
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Table 1: Summary of solubility results obtained by the DSC method in high
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molecular weight systems.
System
Solubility
(%w/w)
PVPK15MN at 97°C
13.2
PVPK15MN at
105°C
PVPK15MN at
117°C
PVPK15MN at
137°C
14.3
17.3
Solubility reported in the
literature (%w/w)
11.0 (predicted by extrapolation
of the solubility curve)
13 (predicted by extrapolation of
the solubility curve)
17.6 (predicted by extrapolation
of the solubility curve)
23.2
25.0 (measured experimentally)
PVPK25IM at 110°C
61.5
60.8 (measured experimentally)
PVPK25IM at 120°C
66.6
66.0 (measured experimentally)
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15
Ref
Tao et al.,
2009
Tao et al.,
2009
Tao et al.,
2009
Tao et al.,
2009
Sun et al.,
2010
Sun et al.,
2010
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The use of conventional DSC for solubility determination has been criticised by some
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authors who consider that the value obtained by this means is actually the solubility
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at the melting temperature (Gramaglia et al., 2005; Qi et al., 2010). They suggest
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that during the DSC scan, the undissolved crystalline phase is continuously dissolving
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in the amorphous matrix giving rise to an overestimation of the actual solubility at
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the annealing temperature. According to these authors, this unwanted dissolution
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during the DSC scan can be limited by using HyperDSC at a fast heating rate.
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However the zero enthalpy extrapolation performed by Gramaglia et al. at 20°C.min -
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1 and
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almost identical plots of the melting enthalpy vs. the mass fraction. Thus, while we
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acknowledge the possibility of some overestimation of solubility, the work of
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Gramaglia et al. (2005) demonstrates that a heating rate of 20°C.min-1 (as used in the
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current study) is sufficient to limit unwanted dissolution upon heating.
400°C.min-1 yielded only a small difference in solubility result (0.4% (w/w)), and
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3.2
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temperature.
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The determination and application of solubility data of low molecular weight
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excipients in an amorphous API (sulfadimidine) has been reported in a previous
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study by our group (Curtin et al., 2013b). We detail further the results and
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methodology in the current work and expand further with other API/low molecular
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weight excipient system. To our knowledge this is the first report of solubility
360
determination for such systems.
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The experimental measurement of the solubility of a low molecular weight excipient
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in an amorphous drug is challenging for several reasons. First of all the drug
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Solubility of a low molecular weight excipient in an amorphous API at room
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amorphisation has to be achievable. Then the API has to remain amorphous during
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the preparation of the API/excipient mixture, the achievement of equilibrium and
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the thermal analysis.
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Moreover even if the amorphous API is stable enough on its own, co-milling with
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crystalline excipient can induce its recrystallisation, as shown by Curtin et al. (Curtin
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et al., 2013a, 2013b). Consequently, milling cannot be used for the preparation of
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the amorphous API/ crystalline excipient mixtures. The sample preparation for
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polymeric matrices, described in the previous section, as well as the melting point
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depression and the annealing method involves the dissolution of the crystalline
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solute in the amorphous matrix until the equilibrium is reached. In contrast, the
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recently reported protocol developed by Mahieu et al. is based on the demixing of
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an initial supersaturated state formed by milling. According to the authors the major
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benefit of this reversed configuration lies in the plastisizing effect of the solute. The
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presence of a high amount of dissolved solute in the amorphous matrix reduces the
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Tg of the initial polymeric matrix an enables a fast achievement of equilibrium.
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The easiest way to form a glass is the melt-quench method. Furthermore co-melting
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the API with the excipient would result in a homogeneous mixture. Considering
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these observations and in line with Mahieu et al.’s results, the sample preparation
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step of the protocol used in the previous section was adapted. The mixtures of
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crystalline API/crystalline excipient were melted on a heating plate in order to form a
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homogeneous liquid phase and subsequently quenched. The resulting solid phases
384
were kept at room temperature for 7 days and were shown to be a mixture of an
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amorphous phase and crystalline excipient by pXRD (data not shown). The heat of
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melting of the crystals increased during the first hours and levelled off after 2 days
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The time frame of the experiment is therefore limited.
387
and remained constant over a week. Therefore, the heats of melting reported here
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are the values measured after only two days. Figure 6 shows the DSC curves
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obtained for the system composed of SD and GA.
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The thermograms present an endotherm corresponding to the melting of GA. Glass
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transitions were also observed for the lowest GA mass fractions at 38°C. This result
392
confirms the hypothesis that the undissolved crystalline excipient is, in all these
393
mixtures, in equilibrium with an amorphous phase that has the same composition.
394
The glass transition of SD is 78°C, the Tg observed around 38°C is presumed to result
395
from the Tg lowering effect of GA reported by Curtin et al. and is the consequence of
396
a high solubility of GA in amorphous SD. The same phenomenon has been observed
397
on the SDAA system with a Tg of 42°C for the saturated composite.
398
The heat of melting measured by DSC has been plotted against the excipient mass
399
fraction for the systems SDGA, SDAA and SDMN (Figure 7). As for the polymer-based
400
systems, a linear relationship is observed with good correlation coefficients
401
(R2>0.99). The solubilities determined by zero enthalpy extrapolation are 34.2%,
402
20.3% and 3.5% for GA, AA and MN respectively.
403
The same protocol has been applied to IMGA, IMAA and IMMN. Figure 8 shows the
404
DSC curves for the IMMN system. Two thermal events are observed: a glass
405
transition at 50°C and an endotherm corresponding to the melting of undissolved
406
MN. The Tgs observed on these thermograms are close to that of amorphous IM
407
(~50°C) and reveals that MN has a low solubility in IM. Indeed, MN has a Tg of 13°C
408
(Willart et al., 2006) and since no Tg reduction is observed on the DSC curves it can
409
be deduced that the amount of MN dissolved in the amorphous matrix is very low.
18
410
The linear regressions for the IMGA, IMAA and IMMN systems are presented in
411
Figure 9. The solubility of crystalline MN in amorphous IM is very low (4.4%), which is
412
consistent with the Tgs observed by the thermal analysis. In contrast the solubility of
413
GA and AA are more than twice as high as that of MN in amorphous IM (11.9% and
414
9% respectively).
415
There is no previous report of experimentally measured solubility in low molecular
416
weight amorphous matrices. Consequently, the validation of the results was carried
417
out by comparing the solubility values determined experimentally with the
418
calculated Hildebrand solubility parameters δ (
419
Table 2). These parameters are based on regular solution theory (Hildebrand and
420
Scott, 1962, 1950).
421
422
Table 2: Hildebrand solubility parameters of APIs and low molecular weight
423
excipients
Compounds SD
δ (MPa1/2)
IM
GA
AA
MN
25.7 26.4 25.8 24.9 47.8
424
425
If two components are found to have similar values then they would be expected to
426
be soluble in each other (Greenhalgh et al., 1999; Hancock et al., 1997). As a
427
consequence, the lower the |Δδ| between the API and the excipient the higher the
428
affinity between the two molecules.
429
430
Table 3 summarises the solubilities and the differences between the solubility
431
parameters of each investigated system. The Hildebrand solubility parameters of the
19
432
dicarboxylic acids are comparable to those of the APIs and in particular the values
433
calculated for GA and SD are almost identical. This observation confirms the high
434
experimental solubilities determined for GA and AA in SD an IM. In contrast the
435
differences between the calculated solubility parameters of MN and the APIs are
436
significant and validate the low solubility observed for these systems. Hence, the
437
experimental values are consistent with the theoretical calculations.
438
439
Table 3: Experimental solubilities and miscibility prediction for low molecular
440
weight systems
System Solubility (%w/w) |Δδ| (MPa1/2)
SDGA
34.2
0.1
SDAA
20.3
0.8
SDMN
3.5
22.1
IMGA
11.9
0.6
IMAA
9.0
1.5
IMMN
4.4
21.4
441
442
Even if this technique is effective at determining the solubility of a crystalline
443
excipient in an amorphous API, it presents some limitations. This method is only
444
applicable for APIs and excipients that are stable upon melting. This problem can be
445
partially solved if the API and the excipient present a eutectic melting. The drug has
446
to be readily amorphisable by the melt-quench method. Moreover the excipient has
447
to crystallise rapidly upon cooling and annealing before the API recrystallization (GA
448
and AA are known to be resistant to amorphisation by melt-quench (Curtin et al.,
20
449
2013b) and amorphous MN is highly unstable (Yoshinari et al., 2003)). If all these
450
criteria are fulfilled, the zero enthalpy extrapolation method can be applied.
451
452
4. Conclusion
453
We have shown that the combination of a careful sample preparation, a sufficiently
454
long annealing and the zero enthalpy extrapolation by DSC leads to a powerful tool
455
for the experimental determination of the solubility of crystalline materials in an
456
amorphous matrix. This protocol has been validated above and at the glass transition
457
temperature by comparison with previously reported results for API solubility in a
458
polymer. This method enabled the determination of the solubility of MN in PVPK15
459
at Tg while other techniques could only measure it above Tg+30°C. Since the sample
460
preparation and the annealing step used in this work are similar to the protocol
461
developed by Tao et al. it would be interesting to measure the solubility at Tg by the
462
scanning method and compare the results with the zero enthalpy extrapolation.
463
Moreover a judicious adaptation of the protocol, in particular for the sample
464
preparation, enabled the application of this technique to the measurement of the
465
solubility in low molecular weight amorphous matrices for the first time. Due to the
466
low Tg of the excipients and the APIs used in this work the solubility could be
467
determined under ambient conditions, since the Tg of the resulting composite was
468
close to room temperature. The solubility values determined by this method
469
confirmed the affinity between the components predicted by theoretical
470
calculations. The quantitative data obtained by the zero enthalpy extrapolation can
471
therefore complete the qualitative information stemming from the Hildebrand
472
solubility parameters.
21
473
474
Acknowledgements: This publication has emanated from research conducted with
475
the financial support of Science Foundation Ireland (SFI) under Grant Number
476
12/IP/1408 and 07/SRC/B1158. The authors would like to thank Mr. Peter O’Connell
477
and Dr. Lidia Tajber for assistance with the HPLC analysis of the SDM, GA and AA
478
systems.
479
480
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