Extraordinary Long-Term-Stability in Kinetically Stabilized Amorphous

Article pubs.acs.org/molecularpharmaceutics

Extraordinary Long-Term-Stability in Kinetically Stabilized Amorphous Solid Dispersions of Fenofibrate Frank Theil, Johanna Milsmann, Samuel O. Kyeremateng, Sankaran Anantharaman, Jörg Rosenberg, and Holger van Lishaut* AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, Germany S Supporting Information *

ABSTRACT: Inhibition of recrystallization of the drug substance in kinetically stabilized amorphous solid dispersions (ASDs) within and beyond shelf life is still a matter of debate. Generally, these ASD systems are considered to be prone to recrystallization, but examples of their long-term stability are emerging in the literature. Since, in some cases, the formation of crystals may impact bioavailability, recrystallization may present a relevant risk for patients as it potentially lowers the effective dose of the formulation. This study shows that such metastable formulations may indeed remain amorphous even after 15 years of storage under ambient conditions. A formulation of fenofibrate stored for 15 years was compared to a freshly prepared batch. A complete physicochemical characterization regarding content, purity, water content and glass transition was conducted. The emphasis of this physicochemical characterization was on crystallinity as a critical quality attribute: polarized light microscopy (PLM) was used as the standard qualitative method and X-ray powder diffraction (XRPD) as the standard quantitative method. An investigation of the crystal growth kinetics by transmission Raman spectroscopy (TRS) was conducted to build a predictive model. The model was applied successfully to predict the observed physical state of the 15-year-old samples. The observations presented here demonstrate that kinetic stabilization alone is able to prevent crystallization in ASDs over prolonged storage periods, suggesting the need for a reassessment of the risk perception for this kind of ASD formulations. KEYWORDS: amorphous solid dispersion, long-term stability, fenofibrate, crystal growth, transmission Raman spectroscopy, predictive model

1. INTRODUCTION During the past decade, more and more poorly water-soluble active pharmaceutical ingredients (APIs) were designed by discovery organizations of pharmaceutical companies, making the lack of solubility of these APIs the main challenge in the development of solid oral dosage forms.1 One way to enhance the water solubility, and therefore potentially bioavailability, that has proven to be successful for many different APIs is the formulation as an amorphous solid dispersion (ASD).2 This technique drastically increases the bioavailability for APIs if dissolution is the rate-limiting step (biopharmaceutical classification system (BCS) II and to a certain extent BCS IV drugs).3 Nevertheless, the crystalline phase of a substance is the thermodynamically stable solid form, rendering the amorphous phase prone to recrystallization. One of the key factors that influence the stability of an ASD is the drug load, which naturally has physical limitations. Since it is highly desirable to keep the pill burden for patients low, it is essential that the drug load of an oral dosage form is as high as possible.4 Stabilizing high drug load formulations to avoid recrystallization and to explore the stability limits of such formulations is a challenging task for pharmaceutical research and industry.5 With a plethora © 2017 American Chemical Society

of poorly water-soluble drug molecules available, ASD-type formulation have become more and more important over the past decade.6 In an ASD, the amorphous form of the API is stabilized by a polymer or another carrier material (e.g., mesoporous silica). On the molecular level the crystallization of the API can be limited by reducing the molecular mobility of the API and disrupting the molecular recognition between the single API molecules.7 Thermodynamically, the driving force of the crystallization is decreased, and the energy barrier of the phase transition is increased.8 Naturally those effects require interaction between the API and the polymer on a molecular level and are not observed in a mere physical mixture.2b For an ASD formulation of an API and a polymer with a given ratio of polymer to crystalline API, the temperature of the final crystal dissolution in the polymer is defined as the solubility temperature.9 Below this temperature, the system represents Received: Revised: Accepted: Published: 4636

August 24, 2017 November 3, 2017 November 6, 2017 November 7, 2017 DOI: 10.1021/acs.molpharmaceut.7b00735 Mol. Pharmaceutics 2017, 14, 4636−4647

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Molecular Pharmaceutics

in a container blender (Bohle GmbH, Gummersbach, Germany). The final blend used for the subsequent extrusion step contained 15% (w/w) of fenofibrate, 82% (w/w) of copovidone K28, 2% (w/w) of Labrafil and 1% (w/w) of colloidal silica. Extrusion of this blend (batch size 12 kg) was performed by using a Micro 18 twin-screw extruder (Leistritz AG, Nürnberg, Germany) with a throughput of up to 1.8 kg/h. Screw speed was 90−104 rpm and the temperature settings of the barrels were 74 °C (= barrel 1, after feeding barrel), 98 °C (barrel 2), 117 °C (barrel 3), 110 °C (barrel 4), and 107 °C (barrel 5). The screw configuration contained one kneading block (forwarding) between barrel 2 and 3 and a second kneading block (reverse-lighted) in barrel 4. The extruder contained a vacuum port and vacuum was applied to the molten extrudate shortly before the extrudate left the extruder. The molten extrudate was formed into bead-shaped pieces of 7.5 mm diameter by a calender. The extrudate was allowed to cool to room temperature after leaving the extruder die. The manufacturing conditions applied in 2002 were recreated for the new sample batch by using a twin-screw 18 mm extruder (ZSK 18, Coperion, Stuttgart Germany) with seven barrels. The screw configuration was constructed in the same way as in the case of the extruder which was used in 2002 (see above). Temperature settings were 70 °C (= barrel 1, after feeding barrel), 110 °C (barrel 2), 145 °C (barrel 3), 145 °C (barrel 4), and 127 °C (barrel 5), 117 °C (barrel 6) and 115 °C (barrel 7). A powder blend containing all ingredients of the final formulation was continuously dosed at 1 kg/h into the extruder by a loss-in-weight feeder system (K-tron, Coperion). 2.3. Tablet Manufacturing. The tablets were prepared by mixing 97.6% (w/w) of the milled extrudate beads (Alpine, Höchst im Odenwald, Germany) with 1.1% (w/w) Aerosil 200 and 1.3% (w/w) sodium stearyl fumarate. This mixture was used to compress football shaped tablets (21 mm × 10 mm) with a target weight of 1092.6 mg. A single-punch tablet press, Fette E1 (Fette Compacting, Schwarzenbek, Germany) and Korsch EK 0 (Korsch AG, Berlin, Germany) was used for the tablets produced in 2002 and 2015, respectively. 2.4. Assay, Degradation. HPLC measurements were performed on a Waters 2695 separations module equipped with a symmetry C18 (75 × 4.6 mm, 3.5 μm dp) column coupled with a Waters 2487 dual wavelength absorbance detector (Waters Corp., Milford, USA). The eluent used was a binary mixture of acetonitrile and aqueous KH2PO4-buffer solution (pH = 3.0) in a linear gradient from 38% to 60% acetonitrile. Ten milligrams of the analyte were dissolved in 100 mL of the eluent by ultrasonication. Twenty-five microliters were injected for analysis. 2.5. Sample Storage. The extrudate pellets and tablets were packaged for storage in brown glass bottles closed with plastic screw caps. The samples were stored in a heated room without air condition. During the summer months the samples were subjected to temperatures up to 30 °C and during the winter months not lower than 18 °C. 2.6. Water Content. The water content of the samples was measured by Karl Fischer-titration using a Titrino 784 (Deutsche Metrohm, Filderstadt, Germany) equipped with a platinum double electrode. Methanol was used as a solvent and titrated to dryness with hydranal composite 5 before each measurement. Afterward, the sample amount of 200 mg milled extrudate/tablet was rapidly transferred into the titration vessel; the vessel was closed and titrated under constant stirring.

an oversaturated solution of the API in the polymer and only above this temperature it is considered to be thermodynamically stable. In the thermodynamically unstable state, the system is prone to amorphous−amorphous phase separation. The process of phase separation will lead to the formation of drugrich domains.10 From these domains in turn crystallization may occur, if the reduced polymer concentration is not able to stabilize the amorphous API. Furthermore, in the literature it is proposed that phase separation has an impact on dissolution and therefore on bioavailability.11 Due to the very slow kinetics of nucleation and growth in the glassy polymer matrix, the drug may be prone to crystallization over a relatively long time scale.12 Recently, we reported the absence of crystal growth in various kinetically stabilized nifedipine formulations after storage for a quarter of a century.13 In the present study, the stability of an ASD of the model drug fenofibrate in copovidone was investigated. With a drug load of 15% (w/w) this formulation is oversaturated and therefore only kinetically stabilized at ambient temperature.10 Samples of this formulation were investigated after the extraordinarily long storage time of 15 years under uncontrolled ambient conditions, which is about 3−5 times longer than the typical shelf life of pharmaceutical products. The stored samples were characterized thoroughly by pharmaceutical standard methods (assay and degradation, drug release) as well as by a wide range of physical characterization techniques to assess crystalline drug content including polarized light microscopy (PLM), differential scanning calorimetry (DSC) and XRPD. The results of these characterizations were compared to the initial release testing and analytical data from freshly prepared samples of the same formulation of fenofibrate. In this encompassing study, no recrystallization of fenofibrate was observed in the aged samples. Having samples at hand which were stored for this exceptionally long time posed a welcome opportunity to investigate the capabilities and accuracy of a predictive crystal growth model. For this purpose, TRS was employed to study the moisture dependency of the crystallization kinetics in the investigated fenofibrate formulation. An extrapolation of the crystal growth under defined temperature and humidity conditions to the uncontrolled ambient storage condition and time proves that this modeling approach has the potential to predict crystal growth in amorphous solid dispersions over a long time scale.

2. METHODS 2.1. Chemicals. Copovidone (K28) was purchased from BASF SE (Ludwigshafen am Rhein, Germany), fenofibrate (≥99%) from Midas Pharma GmbH (Ingelheim am Rhein, Germany); Labrafil was purchased from Gattefosse GmbH (Bad Krozingen, Germany) and Aerosil 200 (SiO2 > 99.8%) from Evonik Degussa GmbH (Essen, Germany). KH2PO4, K3PO4 × H2O, H3PO4, Na2HPO4, NaH2PO4 × 2 H2O, and sodium dodecyl sulfate (SDS) were purchased from SigmaAldrich (St. Louis, USA) in analytical grade. Acetonitrile (HPLC grade) for HPLC measurements was purchased from J.T. Baker (Center Valley, USA). All other organic solvents were of analytical grade and were purchased from Merck KGaA (Darmstadt, Germany). 2.2. Hot Melt Extrusion (HME). The stored samples were manufactured in January 2002. A pregranulated blend of copovidone (95% (w/w)) and Labrafil (5% (w/w)) was mixed with fenofibrate, copovidone and colloidal silica (Aerosil 200) 4637

DOI: 10.1021/acs.molpharmaceut.7b00735 Mol. Pharmaceutics 2017, 14, 4636−4647

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2.11. Transmission Raman Spectroscopy. TRS spectra were measured with a TRS100 spectrometer (Cobalt Light Systems, Oxford, UK) equipped with an electrically cooled CCD (−78 °C). The wavelength of the excitation laser was 830 nm operating at 600 mW for all measurements. Laser illumination spot size was set to 8 mm diameter; small lens collection optics and 0.4 s exposure time were used for data acquisition. Ten acquisitions were taken per spectrum. The spectra were obtained from manually pressed tablets (13 mm diameter, 500 mg, 100 kN). 2.12. Chemometric Method Development. Multivariate analysis of TRS spectra was conducted to quantify the crystalline content of fenofibrate. The Unscrambler X 10.2 (CAMO Software, Oslo, Norway) was used to develop the model and quantify the crystalline content from the acquired spectral data. A data preprocessing routine was used to simplify the data set and establish a more robust model, independent of individual sample fluctuations like optical path length or background. It was found that a combination of second derivative (Savitzky-Golay algorithm, 5 point window, third order polynomial) and unit vector normalization led to the best results. The region of interest was limited to the spectral range between 82 and 309 cm−1 in order to limit the variable load of the model and exclude unwanted matrix effects in the quantification. Different calibration algorithms (principle component regression, partial least-squares regression, support vector machine) were explored. Best results were obtained with partial least-squares (PLS) regression. The model was validated using random window cross-validation with 20 random segments. 2.13. Crystal Growth Investigation. The growth of crystals in the fenofibrate formulation was investigated by TRS. The rapid and nondestructive determination of crystallinity in the samples by TRS makes it possible to follow the crystal growth in individual dosage forms. Manually pressed tablets were placed into sampling trays for the TRS100 instrument. Note that a round glass coverslip was placed under each tablet, as water uptake during the investigation decreases the viscosity of the material. The trays with the samples were directly placed in climate chambers. First a feasibility study was conducted at 40 °C and 75% RH to determine the time scale, maximum crystallization, and repeatability of the technique. The crystal growth study was then conducted at a constant temperature of 25 °C. Four chambers with different humidity conditions were used: 70% RH, 74% RH, 76% RH, and 80% RH. Three tablets were investigated for each environmental condition. The crystallinity was quantified by TRS measurements combined with a chemometric model as described above. The total time for a given degree of crystallization is highly dependent on the humidity conditions and the resulting Tg of the sample. The crystal growth studies were stopped when the equilibrium between crystalline and amorphous material was reached and no further crystal growth was detected. The rate constants of crystal growth were determined by fitting the normalized growth fraction with the formula for phase transfer kinetics developed by Avrami.15 2.14. Dynamic Vapor Sorption. Dynamic vapor sorption (DVS) analysis was performed on a DVS-1000 (Surface Measurement Systems, London, UK). Fifteen milligrams of sample was weighed into the sample cup and dried at 25 °C under nitrogen prior to measurement. The water sorption was determined in the range of 2−85% RH at 25 °C.

2.7. PLM and DSC. Polarized light microscopy experiments were conducted using a DMLM optical microscope (Leica Microsystems, Wetzlar, Germany) equipped with a DFC 320 digital camera (Leica Microsystems, Wetzlar, Germany). Differential scanning calorimetry experiments were performed on a DSC1 (Mettler-Toledo GmbH, Giessen, Germany) coupled with a TC100MT cooling system (Huber Kältemaschinenbau GmbH, Offenburg, Germany). Nitrogen was used as the purging gas. Indium standards were employed for temperature and heat of fusion calibration. Hermetically sealed 40 μL aluminum pans and sample weights between 5 and 10 mg were selected throughout the study. Pierced lids were used in the DSC measurements to determine the API solubility. For evaluation of the Tg under influence of water content the first cycle of the closed pan DSC measurements was used. The samples were measured in the interval from −20 to 140 °C and the heating rate was 10 °C/min. For evaluation of the Tg without the influence of water content, the second cycle of the open pan DSC measurements was used. The samples were measured in the interval from −20 to 200 °C, the heating rate was 10 °C/min, and the cooling rate −10 °C/min. 2.8. Scanning Electron Microscopy. Scanning electron microscopy (SEM) was performed on a TM3000 (Hitachi Ltd., Chiyoda, Japan). The extrudate samples were crushed into splinters directly before measurement. A splinter was placed on a SEM holder equipped with conducting tape. The samples were scanned with 5 kV using the on-board autofocusing and image correction features of the Hitachi TM3000 measurement software. 2.9. Determination of Drug Solubility in Polymers by DSC. A 30% (w/w) fenofibrate ASD was prepared by heating a cryo-milled physical mixture of the API and excipients to 160 °C followed by rapid cooling to room temperature. The homogeneity of the ASD was confirmed by the DSC, as a single Tg was observed. To the milled sample of 30% (w/w) fenofibrate ASD formulation, an appropriate amount of crystalline fenofibrate was added and cryo-milled for 1 min at 10 Hz to prepare physical mixtures containing a final API load of 40% (w/w), 60% (w/w), and 80% (w/w). Next, the DSC methods reported by Yu and co-workers10,14 were applied for the determination of the solubility of the API in the excipient. Prior to DSC measurement, the sample-loaded DSC pans were vacuum-dried (∼20 mbar) for 12 h at 25 °C to remove water. A slow heating rate of 1.5 °C/min from 25 to 120 °C was applied to each mixture to measure the temperature at which the crystalline API completely dissolves into the polymer matrix. The solubility temperature obtained in this fashion is also called dissolution end temperature (Tend).9a Furthermore, each mixture was systematically annealed for 4 h below Tend, and the lowest annealing temperature after which no residual drug crystals are detected was taken as best estimate of the solubility temperature. For the glass transition temperature determination, mixtures were heated to 120 °C at 10 °C/min and cooled at 50 °C/min to −40 °C, followed by reheating to 120 °C to record the glass transition temperature as a midpoint of the transition event. 2.10. X-ray Powder Diffraction. X-ray powder diffraction (XRPD) measurements were performed on an X’pert Pro MPD system (PANalytical, Almelo, Netherlands) with a step size of 0.026° 2θ using Cu Kα radiation (40 kV and 40 mA). Samples were scanned on angular range of 20−25° 2θ, characteristic for the crystalline drug. Reflex analysis was conducted using the X’Pert HighScore 2.2d program from PANalytical. 4638


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Molecular Pharmaceutics 2.15. Drug Release. Dissolution studies were performed using a USP apparatus 2 setup (Vision Elite 8, Hanson Research, Chatsworth, USA) in 900 mL medium (0.05 M sodium dodecyl sulfate in water) at a paddle speed of 75 rpm and a bath temperature of 37 °C. The tablets and extrudate beads were transferred into Japanese pharmacopeia sinkers to prevent the samples from floating. To allow for a better comparison, samples were analyzed using the same conditions as in 2002: Samples were taken after 10, 20, 30, 45, 60, and 90 min and passed through a 0.2 μm cellulose acetate syringe filter (red rim, Whatman, Dassel, Germany) prior to dilution with dissolution medium (6:19, (v/v)). The fenofibrate concentrations were measured by a UV/vis spectrometer (Lambda 35, PerkinElmer, Shelton, USA) at 291 nm against dissolution medium. The drug release was calculated based on the average absorptions of three independently prepared standard solutions. As these conditions did not result in 100% drug release for the tablets and to improve discrimination between extrudate samples, further dissolution experiments were performed using the same setup as before, but with extended sampling times (15, 30, 60, 90, 120, 240, 480, 760, and 1440 min). Drug release during dissolution was quantified by HPLC (Waters 2695, Waters Corp., Milford, USA) using the following method: 10 μL of each sample was injected onto the column (LiChrospher RP-select B, 125 × 4 mm, 5 μm dp, Merck, Darmstadt, Germany). The mobile phase consisted of KH2PO4-buffer solution (pH 2.5)/acetonitrile (30:70, (v/v)) and was applied at 30 °C and a flow rate of 1.0 mL min−1. Fenofibrate was detected by a UV detector at 210 nm. All samples were prepared in triplicate and measured once with the respective setup.

the polymer softens above Tg. To overcome this challenge, the strong plasticizing effect of amorphous fenofibrate, owing to its low Tg (−20 °C), was taken advantage of by first preparing a preloaded 30% (w/w) fenofibrate ASD to serve as a surrogate matrix. The surrogate matrix has a single Tg of 42 °C, which is well below the melting point of the API, and by mixing this matrix with crystalline fenofibrate it was possible to determine the solubility temperature of high drug load formulations of the API in a copovidone/Labrafil matrix. With that data, the empirical model for solubility estimation by Kyeremateng et al. was used, as we experienced this method to be reliable as well as accurate.9a This approach permits the constructing of the solubility curve of a given formulation by DSC measurements and extrapolating the data to storagerelevant conditions. The phase diagram consisting of the solubility curve and the Gordon−Taylor fit of the Tg for the ASD is depicted in Figure 1. The solubility curve was

Figure 1. Phase diagram of the investigated polymer−API system. The solubility temperature at different compositions is depicted as blue squares. The fit of the solubility curve is depicted as a blue line. The measured Tg values of different compositions are depicted as red triangles and the Gordon−Taylor fit as red line. Depending on the position relative to the solubility and Tg curve in the phase diagram four regions can be distinguished as depicted: (i) thermodynamically stable melt, (ii) thermodynamically stable glassy solid, (iii) kinetically stable glassy solid, and (iv) the undercooled or unstable melt, respectively.

3. RESULTS AND DISCUSSION As a fast crystallizer fenofibrate is a common model substance used in the field of ASD research. Despite the large amount of data published studies on the long-term stability of fenofibrate formulations have, to the best of our knowledge, not yet been presented in the current scientific literature. In the following, the results of the investigation of a fenofibrate formulation after 15 years of storage under uncontrolled conditions is presented (Denoted as E1 for stored extrudate and T1 for stored tablets). The results are compared to a freshly manufactured batch of the same composition (denoted as E2 for extrudate and T2 for tablets). The samples were investigated regarding their chemical and physical stability using the pharmaceutical standard quality control techniques. Additionally, the crystalline content of the samples was investigated by PLM and XRPD. As samples stored for this timespan present a unique opportunity to investigate the capabilities of a predictive procedure, the physical stability of the formulation was modeled. For this sake the crystallization kinetics of the fenofibrate formulation were determined for various humidity conditions by TRS and the crystal growth extrapolated to the humidity in the packaging material. 3.1. Solubility of Fenofibrate in the Polymer Matrix. Due to the high viscosity of the glassy polymers typically used in ASDs, determining the solubility of an API is an analytically challenging question. The challenge is further exacerbated if the API’s melting point is lower than the Tg of the polymer excipient matrix, as is the case for fenofibrate (melting point of 81 °C) and the copovidone/Labrafil matrix (Tg is 104 °C). For such a system, the crystalline API will completely melt before

constructed by fitting the experimentally determined solubility data with the equation reported by Kyeremateng et al.10 (details are provided in the Supporting Information). As the solubility temperature approaches Tg of the matrix, the dissolution kinetics of the API typically become much slower than the time scale of the DSC measurement because of the high viscosity of the matrix.10 Under such conditions, an overestimation of the solubility temperature occurs.10 Hence, the experimental solubility temperature for API loads less than 40% (w/w) was not considered for the construction of the solubility curve. The solubility and glass-transition temperature, which mainly determines the thermodynamic as well as the kinetic stability of an ASD formulation, can be visualized in a phase diagram, as shown in Figure 1. Depending on the position relative to the solubility and Tg curve in the phase diagram, four regions can be distinguished: (i) thermodynamically stable melt, (ii) thermodynamically stable glassy solid, (iii) kinetically stable glassy solid, and (iv) the undercooled or unstable melt, respectively. According to the phase diagram, for a 15% (w/w) drug load and a temperature of 25 °C, the fenofibrate formulation is in the kinetically stabilized region (iii) of the 4639


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Another factor impacting the molecular mobility of an API in an ASD is the extent of API-polymer interaction.17 An indicator for the amount of API-polymer interaction is the Flory− Huggins parameter, accessible via the solubility data and the Flory−Huggins equation.14,18 A limitation of the Flory− Huggins approach is that it does not consider directional interactions such as hydrogen bonding and ionic interactions. However, both the API and the polymer are nonionic and do have hydrogen bond donor for hydrogen bond formation therefore the Flory−Huggins approach is a good enough approximation in this case. The calculated Flory−Huggins parameter (χ) for the investigated fenofibrate/copovidone/ Labrafil system is 0.4. A negative χ value indicates attractive API/polymer interaction while a positive value signifies repulsive API/polymer interaction.19 Comparatively, repulsive interaction enhances molecular mobility, decreases miscibility, and induces phase separation and/or crystallization.19 3.4. Drug Release. The performance and differences in product quality of an ASD can be monitored by dissolution. To compare old and new samples, dissolution experiments were performed by using the original photometer (PM) method developed in 2002 (Figure 3i and ii). Based on the release profiles of both the extrudates (lentil shaped beads, 7.5 mm dia.), old and new, no differences can be made out. The difference factor f1 is below 15% and the similarity factor f2 over 50% (Table 2).20 Full release of 100% (w/wAPI) was achieved after 60 min (Figure 3i). A different behavior was observed in the case of the tablets. The drug release differs between the freshly prepared samples and the samples produced 15 years ago. The statistical comparison of this particular dissolution curves leads to f1 factors over 15% and f2 factors below 50% regardless of the used detection method (Table 2). However, very similar release behavior is observed in the case of the old samples before and after the storage period. So no change in quality of the samples can be observed on the basis of the storage time, but can indeed be observed on the basis of to the production year. The dissolution experiments were repeated over a prolonged experiment time of 24 h to achieve full dissolution in the tablets. A more sensitive approach using UV detection by HPLC was used to increase discrimination between old and new samples. For extrudate samples, the second dissolution experiment resulted in a slightly higher and faster drug release rate for the new extrudate (E2) than for the old sample (E1) (Figure 3iii). Compared to the short dissolution experiments, the release profiles of the tablets were similar within the first 90 min (Figure 3iv, inset). Full release was achieved for the new tablets (T2) after 720 min, whereas only a plateau of 94 ± 1% (w/wAPI) was reached for the old tablets after the same period of time (Figure 3iv). Based on the dissolution behavior of the old tablets (T1, Figure 3ii), no change was observed on the basis of the storage time. However, diverse dissolution behaviors of new and old tablets indicate differences in the sample properties (Table 2). Although the new fenofibrate samples were carefully prepared according to the old instructions, not every step could be replicated identically. A small increase in drug release of the extrudate beads measured by HPLC may indicate an alteration in the composition, either due to slightly different conditions during extrusion but more likely due to variations in materials used.21 As the extrudate beads were milled prior to tablet preparation, these differences may be amplified due to the

phase diagram. Based on extrapolation of the solubility curve, fenofibrate is completely insoluble in the matrix at 25 °C, further indicating supersaturation at the given temperature. 3.2. Appearance, Assay, and Water Content. The extrudates stored for 15 years (E1) appear to be quite turbid (Figure 2). Usually, turbidity is a sign for phase separation or

Figure 2. Microphotographs of the stored extrudate (left) and freshly prepared extrudate (right).

crystallization and consequently turbid extrudates require a thorough investigation to understand the root cause of this observation as drawn out in Section 3.6. In 2002 the API content of the tablets was determined to be 100% label claim (LC). After 15 years the API content of the samples is still 100% LC. The sum of impurities in the stored samples is below 0.5% (w/w). Hence, no significant chemical degradation of the API has taken place. The stored fenofibrate samples would still be in compliance with a typical assay specification of 95−105% LC. 3.3. Molecular Mobility. For a given temperature and composition, the molecular mobility of an ASD mainly depends on Tg. The lower the storage temperature with respect to Tg, the lower is the molecular mobility.7,16 The measured closedpan Tg-values for both stored and freshly prepared samples are summarized in Table 1. The Tg (closed pan) of the stored Table 1. Overview of Tg (Closed Pan), Content, Impurities, and Water Content of the Investigated Samplesa

a

sample

E1

E2

T1

T2

Tg at t0/°C Tg at t15/°C content at t0/% LC content t15/% LC sum of impurities at t0/% LC sum of impurities at t15/% LC water content at t0/% LC water content at t15/% (w/w)

N/A 33 N/A 101.2 N/A 0.2 N/A 5.3

40 N/A 99.4 N/A 0.1 N/A 2.8 N/A

46 35 100.4 99.5 0.1 0.2 3.0 4.0

41 N/A 100.4 N/A 0.1 N/A 2.3 N/A

Please note that some values for E1 were not determined in 2002.

sample is 31 °C, approximately 10−15 °C lower than the Tg (closed pan) of the freshly prepared samples. This difference in Tg is expected, because the water content of the stored sample is approximately 1−2% (w/w) higher than that of the freshly prepared sample. The difference between Tg (closed pan) of the stored sample and storage temperature is below 10 °C and as such well below the 50 °C threshold that is assumed to be the point of significant kinetic stabilization.11,12 Due to the water uptake during the storage of the samples, the supersaturation of the API in the matrix increases significantly, making the stability of the sample over the storage period even more noteworthy. 4640


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Figure 3. Dissolution data of extrudates (i), (iii) and tablets (ii), (iv) analyzed by photometer (top row) and HPLC (bottom row). The freshly produced samples are depicted in red. The samples from 2002 are depicted in blue, and the t0 data obtained in 2002 is depicted in green.

Table 2. Similarity ( f1) and Difference ( f 2) Factor for the Presented Dissolution Curves f1/% f 2/%

E1/E2 PM

T1/T2 PM

T1/T1t0 PM

E1/E2 HPLC

T1/T2 HPLC

1 92

64 35

5 82

5 69

24 40

Figure 4. PLM images of the samples from 2002 and the freshly prepared batches. Birefringent spots that vanish after heating to 120 °C are marked by yellow circles. The contrast of the images has been altered by image processing.

increased surface area available in tablets compared to extrudate beads. 3.5. Crystallinity Testing. One of the key characteristics and stability indicators of an ASD is the absence of crystallinity. Since detection and quantification of low amounts of crystallinity in pharmaceutical formulations still remains a challenging task, multiple complementary techniques were applied: PLM imaging was used as the extremely sensitive

standard qualitative technique and XRPD was employed as the standard quantitative technique. A first insight into the crystallinity of the samples can be gained by PLM imaging. The micrographs of the samples at room temperature and heated to 120 °C, well above the melting point of the highest melting polymorph of the API (81 °C), are depicted in Figure 4. In all investigated samples, independently of whether they were produced in 2002 or 4641


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Molecular Pharmaceutics recently, a few birefringent spots are observed in the PLM images of the samples obtained at room temperature. Some of the birefringent structures disappear upon heating of the sample above the melting point of the API and can therefore be assumed to be crystalline fenofibrate. Additional points of birefringence are observed that do not vanish upon heating above the melting point of the API, which can be assigned to cellulose or high melting inorganic impurities. As only a handful of birefringent spots are observed in the PLM images, the amount of those API crystals and impurities is estimated to be well below 0.05% (w/w) by comparison to a spiking series and therefor regarded as negligible. The absence of relevant amounts of crystalline API was further substantiated by XRPD measurements as this analytical technique interrogates crystalline content directly. The diffraction patterns of the API and the investigated samples are depicted in Figure 5. In none of the samples a diffraction

Figure 6. Microscopy images of freshly broken up extrudate pellets in DIC showing round perturbations. The brightness and contrast of the images has been altered by image processing. Figure 5. XRD patterns of fenofibrate (Form I, scaled to 20% original intensity, black), T1 (red), E1 (blue), T2 (green), and E2 (purple).

the matrix upon cooling of the extrudate may explain the observed absence of material at these spots. 3.7. Stability Study and Extrapolation. A sample stored for the exceptionally long time span of 15 years is an outstanding opportunity to test a predictive model. Generally, two environmental factors influence the stability of an ASD: temperature and moisture. Fenofibrate formulations are especially susceptible to crystallization under elevated relative humidity.23 Hence, the crystallization of the formulation under moisture stress is investigated and the results extrapolated to the storage conditions. Different techniques like DSC, XRPD, and Raman spectroscopy have been used in the literature to monitor the crystallization of an ASD.24 Our method of choice is TRS as it allows quantifying crystallinity in an entire dosage form without a sample preparation step like milling. Since an area focused laser beam is used, no burning effects are observed and it is possible to measure the same sample over and over again. Additionally, the short measurement time of TRS compared to, for instance, XRPD is negligible in relation to the storage time of the samples. The measurement therefore has only minimal influence on the crystal growth in the samples. To quantify crystallinity in the fenofibrate formulation by TRS, a chemometric calibration model needs to be build. Since an almost complete crystallization of the drug load was anticipated, a calibration set spanning up to 15% (w/w) crystalline API (cAPI) was prepared. The spectra of three independently prepared samples were measured for each spiking level (see Supporting Information). Figure 8 shows a

peak is observed that matches any peak of the API. Therefore, no residual or reoccurring crystallinity is detected in the investigated formulations by XRPD. The diffraction pattern of both tablet samples shows a broad signal with very low intensity around 22° 2θ. This signal can be attributed to Aerosil 200 used as a glidant in the formulation process, causing an additional amorphous background peaking around 22° 2θ.22 3.6. Phase Homogeneity. Since the turbidity of the samples cannot be explained by crystalline content, the phase homogeneity of the extrudate E1 and E2 was investigated. A microscopic investigation employing differential interference contrast (DIC) (see Figure 6) shows small, round perturbations in the extrudate samples from 2002 as well as in the recently produced ones. As the extrusion was performed under vacuum and based on the composition of the formulation, it is quite likely that those perturbations are microscopically small droplets of Labrafil, which were not entirely mixed with the rest of the matrix. The topology of the perturbations was further investigated by SEM. The SEM image of a freshly broken up pellet of sample E1 (see Figure 7) clearly shows craters of different sizes which explains the observation in the microscopic image well. Sample E2 allows for equivalent conclusions. The identified empty regions or air bubbles in the extrudates explain the turbid optical appearance of the samples, but our investigations give no profound indication of their origin. Since Labrafil is the most lipophilic excipient, it can only be speculated that those bubbles were once filled with Labrafil or a Labrafil-enriched mixture of the extrudate. Diffusion into 4642


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differences in the spectra can be detected in a comparison of the crystal-free and spiked sample of the fenofibrate formulation. This observation does not come as a surprise considering the similarity between the spectra of the amorphous and crystalline phase of the API. Besides a minor broadening of the peaks, the only conceivable difference is a peak in the phonon region of the Raman spectrum at 122 cm−1 and an additional shoulder of the peak at 1600 cm−1 in the spectrum of cAPI. The presence of the excipients in the formulation masks these differences in the spectra of the crystal-free and the spiked formulation. A spectral preprocessing routine was developed in order to assign a region of interest (ROI) and avoid acquisition artifacts. The best results were obtained using a normalized second derivative spectrum (see Methods Section for details). It can be assumed, from the comparison of the spectra of the amorphous and the crystalline API, that two spectral regions of interest can be found: both the phonon region between 82 and 309 cm−1 as well as a region between 1550 and 1600 cm−1 show spectral changes that correlate with the crystalline content of the sample (Figure 9). Only the region between 82 and 309 cm−1 was incorporated in the model, as the ROI around 1600 cm−1 appeared to be influenced by water content in the sample.

Figure 7. SEM images of freshly broken up extrudate pellets showing crater-like structures.

Figure 9. Comparison of TRS spectra (i) and normalized 2nd derivative TRS spectra (ii) showing differences correlating with crystal content of the samples. The sample with 15% cAPI/(w/w) is depicted in blue. The completely amorphous sample is depicted in red. Figure 8. Comparison of the TRS spectra of crystalline fenofibrate (black), amorphous fenofibrate (red)both background corrected; formulation with 15% (w/w) crystalline content (blue), and crystalfree formulation (green).

A PLS model was constructed using the spectra of the calibration set, the sample preprocessing routine and the ROI. The scores, loadings, and correlation plot of the regression are depicted in Figure 10. A table with the figures of merit can be found in the Supporting Information of this article. A good correlation between the reference values of the calibration and the predicted values of the PLS regression is found after three factors: The slope of the regression as well as the cross-

comparison of the TRS spectra of crystalline API, amorphous fenofibrate obtained by melt quenching, the newly manufactured sample of fenofibrate and a spiked sample of the formulation with 15% (w/w) crystalline content. Only marginal 4643


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Figure 10. PLS regression overview: The scores plot of factor 1 and 2 is depicted in (i); scores plot of factor 1 and 3 in (ii). Solid symbols represent calibration samples. Hollow symbols represent validation samples. The loadings plot for the first three factors is given in (iii). Factor one is depicted in red, factor 2 in blue, factor 3 in green and the spectrum of crystalline fenofibrate after preprocessing in black. In (iv) the correlation between predicted and reference values is given. Solid blue squares represent calibration samples and hollow red circles validation samples. The ideal regression is depicted as a black line. The calibration and cross-validation results are depicted as blue and red line, respectively (the lines are superimposed).

validation are very close to one and the offset is near to zero. As the samples are quite randomly distributed around the regression line, a trend in the regression is not suspected. To show the suitability of the TRS model for monitoring crystal growth in the investigated ASD samples two consecutive growth experiments at 40 °C and 75% RH were conducted. For each growth experiment, three tablets of the fenofibrate formulation were placed in a sample holder tray for the TRS instrument and the tray was directly placed in the climatic chamber (note that the tray was placed in a perforated box with lid to avoid the influence of dust particles on the crystallization process). The crystallinity of the samples was then determined in regular intervals by TRS. For the evaluation of the crystal growth kinetics, the obtained weight percentage of crystal growth is expressed as the relative crystallinity α(t), the fraction of crystallinity at a certain time point relative to the final amount of crystallization in the sample. The typical sigmoidal curve of the crystal growth process was fitted according to the Avrami equation:15 α(t ) = 1 − exp[−k(t − t0)n ]

Figure 11. Crystal growth of fenofibrate in the investigated formulation at 40 °C and 75% RH. Two measurement series are depicted. The points represent the average crystallinity in the three samples at each time point. The lines represent the Avrami fit of the crystal growth kinetics.

(1)

lization kinetics at a constant temperature of 25 °C were investigated. Samples were exposed to four different humidity conditions 70, 74, 76, and 80% RH. The growth studies were concluded when the crystallization reached the equilibrium point of crystalline and amorphous fenofibrate in the investigated formulation (∼11.5% (w/w)). The time until the equilibrium is reached spans from 10 days in case of 80% RH to over seven months for 70% RH. The sampling points were distributed over the whole timespan of the crystal growth study. Three independent samples were investigated for each environmental condition where crystal growth was sufficiently slow to permit continuous sampling. In case of the 80% RH, two sample sets consisting of three samples per set were investigated. The two sample sets were placed into the stability chambers at different starting points to ensure sampling coverage of the entire crystallization time.

where k is the rate constant, t0 an offset time, and n the Avrami exponent related to the dimension of crystal growth. In Figure 11 the crystal growth curves of the two sample sets stored at 40 °C and 75% RH is depicted. Nearly the same values of crystalline content are obtained at each time point for both measurement series. The equilibrium concentration of crystalline API at the end of the measurement series is the same for both experiments. For the fitting procedure the Avrami exponent was set to 3. This value gives the best fitting results, as already acknowledged for other fenofibrate formulations in the literature.24a Fitting the kinetic traces of both experiments with the Avrami equation (eq 1) leads to almost identical rate constants in the same order of magnitude. To extrapolate the kinetic constant of the crystal growth in this particular formulation to the storage conditions, crystal4644


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Figure 12. Crystal growth kinetics of the fenofibrate formulation stored at 25 °C and 80% RH (i), 76% RH (ii), 74% RH (iii), and 70% RH (iv).

The crystalline content over time as well as the Avrami fit of the crystal growth for all four investigated environmental conditions is depicted in Figure 12. In all studied cases, the crystal growth corresponds closely to the expected sigmoidal behavior. The end point content of cAPI is nearly the same for all the investigated environmental conditions. As expected, the obtained rate constants for the phase transition increase significantly with higher relative humidity as does the crystallization half-life and therefore water uptake of the sample (Table 3).

where f T is the temperature specific factor and the rate constant only dependents on the water content of the sample. Eq 3 allows for a linear fit of the natural logarithm of the rate constant in relation to the water content of the sample. In Figure 13 this fit is performed on the rate constants obtained

Table 3. Maximal cAPI Content and Kinetic Fit of the Different Crystal Growth Experiments and Crystallization Half-Life RH/% 80 76 74 70

k/d−3

cAPImax/% (w/w) 11.2 11.4 11.3 11.2

± ± ± ±

0.1 0.2 0.2 0.2

5.8 1.8 1.4 3.7

± ± ± ±

0.3 0.2 0.1 0.2

× × × ×

t1/2/d 10−3 10−4 10−4 10−7

6.5 11.7 13.2 79.4

Figure 13. Linear fit of the logarithm of the rate constant in relation to the moisture uptake of the sample. (Note that the fit is weighted for the deviation of the single rate constants.)

From the data obtained the humidity-dependence of the rate constant can be calculated. Genton and Kesserling25 developed an empirical expression to model the effects of temperature and moisture on solid state reactions: E ln(k T , h) = ln(A) − a + bh RT

from the crystallization experiments presented above. Since this fit is based on an empirical formula (eq 2) and contains further assumptions as well as experimental fluctuations, this approach is naturally far from being accurate. Fortunately, long-term data on the stability of this formulation is at hand to assess the validity of this approach. Since the moisture uptake of the sample under the long-term storage conditions is minimal, xw is still in the plateau region of the water sorption isotherm (see DVS data in SI). The rate constant can therefore be directly derived from f T with reasonable accuracy. Incorporating the deviation of f T, three rate constants can be calculated: a median rate constant and two constants corresponding to the boundaries of the fitted value. The crystal growth in the sample extrapolated over the storage period for all three cases is depicted in Figure 14. Three different scenarios for the phase state of the API in the samples after storage can be deduced from the extrapolation.

(2)

where kT,h is the temperature and moisture dependent rate constant, A is the Arrhenius constant for the reaction, Ea the activation energy, and R the gas constant. The humidity dependent term consists of b, a moisture sensitive constant independent of temperature and h, the humidity. As stated by Zhang et al.26 it is more suitable to use the actual water content xw from the moisture isotherm due to the nonlinear relationship between RH and the water content of the sample. The empirical formula by Genton and Kesserling (eq 2) can be further simplified for the present application as the temperature is constant: ln(k xw) = fT + bx w

(3) 4645


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brate even after 15 years of storage. This observation shows again that a kinetically stabilized ASDs can indeed be resistant to recrystallization, even after a prolonged storage period exceeding the shelf life typically desired for pharmaceutical drug products.13 Even at storage temperatures of only 10 °C below the Tg, the molecular mobility in the investigated ASDs was not sufficient to induce crystallization on the observed time scale. Our work with the model compound fenofibrate poses an example showing that kinetically stabilized ASDs can be formulated to be long-term stable. The application of TRS permitted the investigation of recrystallization in an individual dosage form. Crystal growth kinetics obtained at different moisture levels were used for an extrapolation of the crystal growth in the present formulation by the Genton-Kesserlingapproach. In the investigated case this approach, based on an empirical framework, overestimated the crystal growth by orders of magnitude.

Figure 14. Extrapolation of crystal growth. The red curve represents the extrapolation for kmax = 6.88 × 10−11 d−3, the blue curve the extrapolation for kmed = 2.81 × 10−13 d−3, and the green curve the extrapolation for the minimum value of kmin = 1.15 × 10−15 d−3.

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ASSOCIATED CONTENT

S Supporting Information *

For kmax, the crystal growth has already reached equilibrium after 15 years of storage. This scenario can clearly be excluded as the stored samples did not contain this amount of crystalline material. For the median value of k, the crystal growth in the samples would just be in the onset period. The calculated value of crystalline content after 15 years is 0.5% (w/w). This amount would clearly be visible in PLM and just detectable by other techniques like XRPD. Furthermore, the observed crystalline content in the stored samples does not support this case. For kmin, almost no detectable levels of crystallization are observed in the samples after the storage period. The amount of grown material is in the magnitude of 10−3 % (w/w) and would barely be visible in PLM. This latter scenario therefore most closely resembles the phase state of the fenofibrate formulation after 15 years of storage. The actual crystallinity in the studied fenofibrate formulation after 15 years of storage is minimal. Only a few crystals are observed in PLM and no crystallinity was detected by XRPD. The extrapolation of the data therefore overestimates the crystal growth by orders of magnitude. On the one hand, the inaccuracy of the model is not surprising, as it is based on an empirical approach and extrapolating over this vast time span. On the other hand, however, it shows that kinetically stabilized formulations are far more reluctant to recrystallize than generally assumed.

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.7b00735. Solubility curve, list of A and C fitting variables, DSC thermograms, TRS calibration, and dynamic vapor sorption (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +49 621 589 2037; Fax: +49 621 589 62037; E-mail: [email protected]. ORCID

Frank Theil: 0000-0002-9396-3118 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Numerous AbbVie employees of NCE Analytical R&D and NCE Formulation Sciences were involved in manufacturing of the samples as well as routine analytics. Their contribution to this work is highly appreciated. All authors are employees of AbbVie. The design, study conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.

4. CONCLUSION In this study, kinetically stabilized amorphous solid dispersions of fenofibrate were characterized regarding their chemical and physical stability as well as their dissolution performance after 15 years of uncontrolled storage. An in-depth characterization was conducted using state-of-the-art methods, comparing the results with a remanufactured sample batch. Original data was compared to analytical results after storage. Using the established techniques PLM and XRPD, no relevant level of recrystallization could be detected in the samples after 15 years of storage. This finding was supplemented by TRS as a complementary analytical technique. TRS was also used as a suitable tool to investigate crystal growth. By studying the crystal growth kinetics for different moisture levels, a crystal growth prediction for the storage condition was made and tested against the phase state of the 15-year-old samples. The findings presented here demonstrate the stability of thermodynamically unstable extrudates of amorphous fenofi-

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REFERENCES

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