Test method for crystallinity in amorphous pharmaceutical compositions

Abstract

Provided is a method for testing a pharmaceutical composition for the presence or absence of active pharmaceutical ingredient (API) crystallinity in an amorphous solid dispersion or solid solution using UV / vis spectroscopy. The test can be performed independently or during the manufacturing process of the pharmaceutical composition. The prediction model provides a quantitative analysis of the amount of crystalline API based on UV / vis data of corresponding reference samples. Also provided is an apparatus for manufacturing a pharmaceutical composition.

Description

[0001] This application claims priority to GB1901579.1 filed on February 5, 2019, the contents and elements of which are incorporated herein by reference for all purposes. Technical Field

[0002] The present invention relates to the presence of crystallinity in otherwise amorphous pharmaceutical compositions. The present invention relates, among other things, to a method of detecting and optionally quantifying the crystallinity of otherwise amorphous pharmaceutical compositions. Background Art

[0003] The pharmaceutical industry produces products that are required to meet very strict quality standards. This is because adverse reactions from substandard products pose a widespread threat to public safety. Previously, there was a higher incidence of substandard drug compositions entering the market. In an attempt to reduce the incidence of substandard drug compositions entering the market, the pharmaceutical industry has seen extensive and increasing regulatory requirements.

[0004] Pharmaceutical companies typically have dedicated quality control departments to ensure that their pharmaceutical compositions meet relevant regulatory standards. Meeting regulatory standards can impose a huge economic burden due to the time, personnel, and equipment required. What is desired is to reduce the amount of time and money required to meet regulatory standards without compromising quality.

[0005] Process Analytical Technology (PAT) is used to effectively design and control pharmaceutical processes by monitoring specific quality indicators and parameters. The pharmaceutical industry is constantly evolving and there is regulatory pressure to move from batch manufacturing to continuous manufacturing. PAT is particularly relevant to emerging continuous manufacturing methods.

[0006] There are many factors that are evaluated in the quality control of pharmaceutical compositions. One of these factors is the physical form. Active pharmaceutical ingredients (API) can exist in a variety of different solid forms, including polymorphs, solvates, hydrates, salts, cocrystals, and amorphous solids. Each form exhibits unique physicochemical properties that can greatly affect bioavailability, manufacturability, purification, stability, and other properties.

[0007] Crystallinity, especially crystal polymorphism, can greatly affect the solubility, bioavailability, and stability of many APIs. Significant increases in drug absorption kinetics and overall bioavailability have been observed by co-formulating small molecule APIs with water-soluble polymers.

[0008] It is therefore of great interest to produce "amorphous solid dispersions" of APIs, in which crystalline material is rendered amorphous by incorporation into a molten polymer phase by virtue of being "dissolved" (ie molecularly dispersed) and no longer crystallizing.

[0009] Effective mixing and sufficient mechanical energy are required to produce a well-dispersed amorphous product. However, determining the extent of dissolution / dispersion (especially in an in-line setting) is not straightforward.

[0010] Typically, to determine the level of residual crystalline material present in a solid sample, the solid first needs to be ground into a uniform powder and then analyzed in a powder X-ray diffractometer. Powder XRD is not a fast process, it is performed off-line and typically takes 15 min to 1 hour to obtain results.

[0011] It is also possible to use Raman spectroscopy to measure the level of crystallinity in such solid samples, for example see Thiel et al., Manufacturing Amorphous Solid Dispersions with a Tailored Amount of Crystallized API for Biopharmaceutical Testing, Mol. Pharmaceutics, 2018, 15(5), pp. 1870-1877, which reports a study of crystal growth of fenofibrate tablets over time. However, Raman spectroscopy is difficult to use in an online manufacturing environment due to the complexity associated with lasers, laser safety, and the generally long integration times required to obtain useful spectra.

[0012] In view of the above, there is a need for improved methods and apparatus for monitoring and manufacturing high-quality amorphous pharmaceutical compositions.

[0013] WO 2016 / 118633 A1 describes the quantification and preparation of pharmaceutical grade cantharidin. US 2008 / 0165354 A1 describes a method and apparatus for dissolving a solid substance in a liquid.

[0014] The use of online UV / vis spectroscopy as a fast-working process analytical technology (PAT) during early product development using hot melt extrusion is well known, see Pharmaceutics 2018, 10, 166.

[0015] The present disclosure is designed in view of the above considerations. Summary of the invention

[0016] In a first aspect of the present invention, there is provided a method for generating a predictive model for determining the amount of crystallinity of an API in an amorphous solid dispersion or solid solution, the method comprising the steps of: (i) subjecting a plurality of reference samples of the dispersion or solution spanning a range of API crystallinity to UV / vis spectroscopy, (ii) measuring the reflectance and / or transmittance spectrum of each reference sample, and (iii) processing the spectra collected in step (ii) to generate a predictive crystallinity model.

[0017] References herein to "dispersion" and "solution" refer to "amorphous solid dispersion" and "solid state solution", respectively.

[0018] By generating a predictive model in this way, it is possible to determine the amount of quantitative crystallinity of an API in a dispersion or solution, such as in the method provided in the first aspect of the invention.

[0019] In some cases, the number of reference samples is 5 or more.

[0020] In some cases, the spectrum is pre-processed prior to step (iii) to normalize and / or smooth the spectrum.

[0021] In some cases, the spectrum of the reference sample is processed to derive features related to crystallinity across at least a portion of the crystallinity range.

[0022] In some cases, the feature includes: at least a first principal component derived from a principal component analysis (PCA) of the spectrum, optionally wherein the variance of the crystallinity of the first principal component is substantially linear over the range of crystallinity of the plurality of dispersions or solutions; or a lightness value L* in a CIELAB color space derived from the spectrum.

[0023] In a second aspect of the present invention, there is provided a method for testing a pharmaceutical composition comprising an API in an amorphous solid dispersion or solid solution for the crystallinity of the API, the method comprising the steps of: (i) subjecting the dispersion or solution to UV / vis spectroscopy, (ii) measuring the reflection and / or transmission spectra, and (iii) determining the presence or absence of crystallinity of the API by comparing the measured reflection and / or transmission spectra with the expected spectra of a completely amorphous sample.

[0024] It has been found that the transmission / absorbance and reflection of amorphous solid dispersions or solid solutions are related to the crystallinity of the API. As used herein, UV / vis spectroscopy does not rely on electronic transitions between orbitals. Without wishing to be bound by theory, the present invention relies on the scattering of light by API crystals present in otherwise amorphous pharmaceutical compositions. One advantage is the rapid and inexpensive detection of API crystallinity of otherwise amorphous dispersions or solutions.

[0025] In some cases, when crystalline API is found to be present, there is a step of determining the amount of crystals in the dispersion or solution by comparing the observed spectrum to a predictive model (eg, a standard curve).

[0026] In some cases, the predictive model is according to the first aspect of the invention.

[0027] In some cases, comparing the observed spectrum to the predictive model includes processing the observed spectrum in the same manner as the spectra of the plurality of reference samples.

[0028] In some cases, the amount of crystallinity in the dispersion or solution is measured to be 50 wt% and less, such as 25 wt% and less or 20 wt% and less or 15 wt% and less.

[0029] In some cases, the amount of crystallinity in the dispersion or solution is measured at 1 wt% and above, such as 2 wt% and above or 3 wt% and above or 5 wt% and above.

[0030] In a third aspect of the present invention, a method for manufacturing a pharmaceutical composition is provided, the method comprising the steps of: (i) forming an API into an amorphous solid dispersion or a solid solution, (ii) testing the dispersion or solution one or more times for the crystallinity of the API according to the second aspect of the present invention, and (iii) when the dispersion or solution has an amount of crystallinity within an acceptable range, processing the composition into a finished pharmaceutical product.

[0031] By testing a dispersion or solution one or more times for API crystallinity, the advantage is that high quality pharmaceutical compositions that meet required regulatory standards can be manufactured with increased reliability and consistency. Due to improved manufacturing efficiency, waste of time, money and resources is reduced.

[0032] In some cases, forming the API into a dispersion or solution is performed by extrusion, ball milling, or spray drying; and / or testing the dispersion or solution one or more times for the presence or absence of crystallinity is performed in-line.

[0033] In some cases, the forming is performed by extrusion and the testing is performed at one or more of the API input point, upstream of the extrusion point, and the extrusion point.

[0034] In some cases, the forming is performed by ball milling in a ball mill having one or more clearing points, wherein the testing is performed with the one or more clearing points substantially perpendicular to the axis of motion.

[0035] In some cases, the forming is performed by spray drying and the testing is performed at one or more of the API input point, the atomization point in the drying chamber, or the settling point after atomization.

[0036] In some cases, the acceptable range of the crystallinity is 1 wt% or less. The acceptable range of the crystallinity may also be 0.25 wt% or less, 0.5 wt% or less, 2 wt% or less, or 3 wt% or less.

[0037] In some cases, the API input to the screw extruder, ball mill or spray dryer is automatically adjusted, as necessary, to ensure that the crystallinity is within the acceptable range.

[0038] In some cases, the speed of the screw extruder, ball mill or spray dryer is automatically adjusted when necessary to ensure that the crystallinity is within the acceptable range.

[0039] In some cases, the temperature of the extruder barrel or spray dryer is automatically adjusted, when necessary, to ensure that the crystallinity is within the acceptable range.

[0040] In some cases, UV / vis reflectance and / or transmission are measured continuously, for example 7 times per second, 5 times per second, or 2 times per second.

[0041] In some cases, the reflection and / or transmission spectra are measured at a wavelength of 210 to 800 nm, such as 300 to 700 nm, preferably 315 nm to 400 nm (UVA).

[0042] In some cases, only the reflectance spectrum is measured.

[0043] In some cases, only the transmission spectrum is measured.

[0044] In some cases, the particle size of the dispersion or solution is measured before UV / vis spectroscopy. Known methods for sizing dispersions or solutions include sieve analysis, direct imaging and laser diffraction. In the present disclosure, a Mastersizer (Malvern Instruments) laser diffraction device is used.

[0045] In some cases, the dispersion or solution is sized to match the size of one or more reference samples of known crystallinity, where the reference samples match the API and vehicle of the dispersion or solution.

[0046] In some cases, the API is a compound with a molecular weight of 2000 g / mol or less, such as a small molecule drug with a molecular weight of 1000 g / mol or less. In some cases, the API is a compound with a molecular weight of 100 g / mol or more, such as a compound with a molecular weight of 200 g / mol or more.

[0047] In some cases, the API is at least 95% pure, such as at least 97% pure or at least 99% pure, prior to incorporation into the dispersion or solution.

[0048] In some cases, the API comprises 5 wt% or less water. Preferably, the API comprises 3 wt% or less water, such as 1 wt% or less water.

[0049] In some cases, the API is a non-nucleoside reverse transcriptase inhibitor (NNRTI), preferably etravirine (ETR), or a non-steroidal anti-inflammatory drug (NSAID), preferably piroxicam (PRX). The API can be any class of orally administrable drugs having at least one crystalline form.

[0050] In some cases, the carrier of the dispersion or solution includes an amorphous polymer.Of course, an amorphous solid dispersion or solid solution includes a carrier in which the other components are dispersed or "dissolved".

[0051] In some cases, the amorphous polymer is one or more of a cellulosic polymer, a vinyl polymer, a polymethacrylate polymer, and a polyalkylene glycol polymer.

[0052] In some cases, the amorphous polymer is one or more of the following: ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), HPMC acetate succinate (HPMCAS); polyvinyl acetate phthalate; polymethacrylate; polyalkylene glycols, such as polyethylene glycol (PEG), copolymers of PEG, polypropylene glycol (PPG), poloxamers (a triblock polymer having a central hydrophobic PPG block flanked by two hydrophilic PEG blocks), soluplus (PEG-polyvinyl acetate-polyvinyl caprolactam graft copolymer (PVAc-PVCap-PEG)); polyvinyl pyrrolidone (povidone), copovidone, vinyl pyrrolidone-vinyl acetate copolymers, and linear random copolymers of N-vinyl-2-pyrrolidone and vinyl acetate (e.g., 60:40).

[0053] In some cases, the amorphous polymer is one or more of the following: VA 64, 12PF, 17PF, 30. 90F, SR, MAE 100P, IR, Protect, P407, P407 micro, P188, P188 micro, PEG grades, RH 40 and TPGS (as supplied by BASF).

[0054] In some cases, the carrier of the dispersion or solution comprises 5 wt% or less water. Preferably, the dispersion or solution comprises 3 wt% or less water, such as 1 wt% or less water.

[0055] In some cases, the dispersion or solution comprises 5 wt% or less water. Preferably, the dispersion or solution comprises 3 wt% or less water, such as 1 wt% or less water.

[0056] In a fourth aspect of the invention, there is provided an apparatus for forming a pharmaceutical composition as an amorphous solid dispersion or solid solution, comprising a quality control system for testing the amount of crystallinity of the API in the composition by one or more UV / vis spectrometers configured to measure reflection and / or transmission intensity.

[0057] By using such an apparatus, the amount of crystalline API in an amorphous solid dispersion can be determined quickly and inexpensively without the need for a separate apparatus. Thus, quality control is an integral part of the apparatus rather than a separate off-line entity.

[0058] In some cases, the equipment comprises a screw extruder, a ball mill or a spray dryer, wherein the or each UV / vis spectrometer is located at an online measurement point to measure the reflection and / or transmission of the dispersion or solution. By positioning the UV / vis spectrometer online, the results of the reflection and / or transmission measurements can be immediately used to modify the extrusion parameters as required.

[0059] In some cases, the apparatus comprises a screw extruder, and the UV / vis spectrometer or at least one of the UV / vis spectrometers is configured to measure reflectance and / or intensity at one or more of the API input point, upstream of the extrusion point, and the extrusion point.

[0060] In some cases, the apparatus comprises a ball mill having one or more transparent points, wherein the UV / vis spectrometer or at least one of the UV / vis spectrometers is configured to measure reflection and / or transmission through the one or more transparent points and substantially perpendicular to the axis of motion.

[0061] In some cases, the apparatus comprises a spray dryer, and the UV / vis spectrometer or at least one of the UV / vis spectrometers is configured to measure reflection and / or transmission at one or more of an API input point, an atomization point in a drying chamber, and a settling point after atomization.

[0062] In some cases, the UV / vis spectrometer or each UV / vis spectrometer is photonically connected to a probe at the or each measuring point via an optical fiber. The tip of each probe may include a sapphire window. Preferably, the length of each optical fiber is 20 meters or less. The UV / vis spectrometer may include a xenon flash lamp for illumination via optical fiber.

[0063] In a Reflection Polymer Melt Probe (RPMP), each optical fiber may have six peripheral glass fibers for illumination and one central glass fiber for reflection. The light propagates through the peripheral glass fibers to the measurement point and returns via the central glass fiber for reflection.

[0064] In a Transmission Polymer Melt Probe (TPMP), there are two separate units placed at a certain distance along the path of a solution or dispersion. One unit provides illumination while the other collects the light transmitted through the solution or dispersion along the path. The distance between the two units can be varied to optimize the measurement of either the dispersion or solution conditions in the path.

[0065] In some cases, the apparatus is configured to automatically adjust the API input to the screw extruder, ball mill or spray dryer when required in response to online measurements by the or each UV / vis spectrometer.

[0066] In some cases, the apparatus is configured to automatically adjust the speed of the screw extruder, ball mill or spray dryer when required in response to online measurements of the or each UV / vis spectrometer.

[0067] In some cases, the apparatus is configured to automatically adjust the temperature of the screw extruder, ball mill or spray dryer when required in response to online measurements of the or each UV / vis spectrometer.

[0068] In some cases, the spectrometer is configured to measure reflected and / or transmitted intensity over a range of 210 to 800 nm, such as 300 to 700 nm or 315 nm to 400 nm (UVA).

[0069] In some cases, the or each UV / vis spectrometer is configured to measure reflection and / or transmission continuously, for example at least once per second, at least twice per second, at least five times per second or at least seven times per second.

[0070] In certain cases, the apparatus is for use with a method according to the third aspect of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] In order that the present invention can be understood, and in order that further aspects and features thereof can be appreciated, embodiments illustrating the principles of the present invention will now be discussed in more detail with reference to the accompanying drawings, in which:

[0072] Figure 1 Five UV / vis transmission spectra from 230 to 810 nm are shown for 15, 18, 20, 23 and 25 wt% PRX samples. An overall increase in absorbance is seen with increasing amounts of PRX, with a particularly large increase in total absorbance observed between 23% and 25% PRX.

[0073] Figure 2 Five XRD spectra of pure solid PRX, Collidan VA64 and 20, 25 and 30 wt% PRX mixtures obtained on a Bruker instrument are shown. The XRD fingerprint trace of crystalline PRX is first observed in the 30% PRX spectrum.

[0074] Figure 3 HMPC-E5 ( Overlaid UV / vis spectra of a polymer mixture of hydroxypropyl methylcellulose (hydroxypropyl methylcellulose) and sodium stearyl fumarate (SSF).

[0075] Figure 4 Shown are superimposed UV / vis reflectance spectra of ETR dispersed in hydroxypropylmethylcellulose (HMPC-E5) where the total amount of ETR was 20 or 25 wt%.

[0076] Figure 5A good correlation between L* values ​​and crystallinity is shown for 13 unground ETR samples, each with a different degree of crystallinity, as pre-determined by Raman spectroscopy obtained on a Kaiser instrument. The total amount of ETR in each sample (including amorphous and crystalline content) is 25 wt%. The unground samples are direct solid monolithic forms produced upon solidification after extrusion.

[0077] Figure 6 Shown with Figure 5 Reflection UV / vis transmission spectra of the same 13 ETR samples from 220 to 800 nm.

[0078] Figure 7 The results obtained on the Rigaku instrument are shown in Figure 5 XRD spectra of the same 13 ETR samples.

[0079] Figure 8 Shows Figure 5 UV reflectance spectra of 5 of the 13 ETR samples with essentially no crystallinity (<1% as determined by Raman spectroscopy). Good reliability and reproducibility of the overall spectral shape and reflectance between these very similar samples was observed.

[0080] Fig. 9 A plot of the loading contribution to Factor 1 (the first principal component derived from PCA of the reflectance spectra of the ETR-containing samples as described in Method 3) (y-axis) is shown versus the wavelength (in nm) from 290 to 400 (x-axis). As shown, Factor 1 provides the first eigenvector that explains the variance in the data set.

[0081] Fig.10 A plot of variance (y-axis) versus factors in the PCA (x-axis) is shown, showing that Factor 1 and Factor 2 explain approximately 98% and 2% of the variance of the data set, respectively.

[0082] Fig.11 Shown is a scatter plot of Factor 2 (y-axis) versus Factor 1 (x-axis) from the PCA analysis in Method 3. As can be seen, the samples are clustered according to crystallinity (i.e., 2.5% crystallinity samples (squares), 5% crystallinity samples (circles), 10% crystallinity samples (triangles), and 20% crystallinity samples (diamonds)).

[0083] Fig.12 Shown is a plot of the crystallinity predicted by a factor of 1 (y-axis) versus the known (reference) crystallinity level of the sample (x-axis). The inset shows the linearity of the correlation. DETAILED DESCRIPTION

[0084] The features disclosed in the preceding description, or in the following claims, or in the accompanying drawings, expressed in their specific form or in terms of means for performing the disclosed functions, or methods or processes for obtaining the disclosed results, may be used alone or in any combination of these features, as the case may be, to realize the invention in its multiple forms.

[0085] Although the present invention has been described in conjunction with the above exemplary embodiments, it will be clear to those skilled in the art that many equivalent modifications and changes will be made based on this disclosure. Therefore, it is considered that the above exemplary embodiments of the present invention are illustrative rather than restrictive. Various changes can be made to the embodiments without departing from the scope of the present invention.

[0086] To avoid any doubt, any theoretical explanations provided herein are provided for the purpose of enhancing the reader's understanding. The inventors do not wish to be bound by any of these theoretical explanations.

[0087] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0088] Throughout this specification and the claims that follow, unless the context requires otherwise, the words “have”, “comprise” and “include” and variations such as “having”, “comprises”, “comprising” and “including”, will be understood to imply the inclusion of a mentioned integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0089] It must be noted that, as used in the specification and the appended claims, the singular forms "a / an" and "the" include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when a value is expressed as an approximation by using the antecedent "about," it will be understood that the particular value forms another embodiment. The term "about" with respect to a numerical value is optional and means, for example, + / - 10%.

[0090] The words "preferred" and "preferably" as used herein refer to embodiments of the present invention that may provide certain benefits in certain circumstances. However, it should be understood that other embodiments may also be preferred under the same or different circumstances. Therefore, the recitation of one or more preferred embodiments does not mean or imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the present disclosure or the scope of the claims.

[0091] Example

[0092] Method 1 - Online crystallinity detection of piroxicam in Colidan VA64

[0093] The solubility maximum of a mixture of the nonsteroidal anti-inflammatory drug (NSAID) piroxicam (PRX) and the carrier polymer Colidan VA 64 was evaluated using a twin screw extruder. The mixture was continuously analyzed as it passed through the extruder screw using an online UV / vis spectrometer system, and the input of PRX was adjusted until crystallinity was first detected.

[0094]

[0095] Formula 1.4-Hydroxy-2-methyl-1,1-dioxo-N-pyridin-2-yl-1$l^{6},2-benzothiazine

[0096] -3-Formamide (PRX)

[0097] The samples were analyzed by UV / vis spectrometer in transmission mode ( Figure 1 ), and XRD spectra of the same samples were also obtained for comparison and verification ( Figure 2 ). XRD samples require offline grinding and analysis, while the advantage of UV / vis is that it can be performed quickly online without grinding.

[0098] UV / vis transmission spectra of 15, 18, 20, 23 and 25 wt% PRX samples were obtained. There was a clear increase in total absorbance between the 23 and 25 wt% PRX samples. This correlates with the observation that the mixture was amorphous, homogeneous and transparent at PRX loadings below 25 wt%. However, at 25 wt% PRX, the first microcrystalline domains were observed, resulting in increased scattering and decreased transmitted light (i.e., increased absorbance).

[0099] XRD spectra of pure solid PRX, Collidan VA64, and each of the 20, 25, and 30 wt% PRX blends were obtained on a Bruker instrument. In contrast, XRD did not detect the presence of crystallinity in the 25 wt% PRX blend. Only at 30 wt% PRX loading, well above the maximum solubility, when significantly higher crystallinity is present, does the XRD spectrum first show peaks related to the pure XRD spectrum of PRX. The Collidan VA64 spectrum indicates that the polymer component of the blend is amorphous.

[0100] This experiment shows that UV / vis can have a higher sensitivity to low amounts of crystallinity compared to XRD.

[0101] Method 2 - UV / Vis Calibration Using a Ground Crystalline ETR Dilution Series

[0102] Etravirine (0.82271 g), sodium stearyl fumarate (0.03291 g) and HMPC-E5 (2.444 g) were added to a small sealable plastic bag to provide a 25 wt% ETR mixture. ETR was 100% crystalline. HMPC-E5 was cryogenically ground for 20 minutes and dried before use.

[0103]

[0104] Formula 2. 4-[6-amino-5-bromo-2-(4-cyanoanilino)pyrimidin-4-yl]oxy-3,5-dimethylbenzonitrile (ETR)

[0105] The particle size distribution of the components was measured using a Mastersizer and is shown in the table below.

[0106] Components D10 D50 D90 Crystalline Etravirine (ETR) 8μm 26μm 87μm HPMC-E5 (cryogenic grinding for 20 minutes) 3μm 17μm 60μm

[0107] Table 1. Particle size distribution of components.

[0108] The sealed bag was alternately kneaded and shaken for a total of 2 minutes. The resulting powder was used in a serial dilution series to provide mixtures with 20, 10, 5, 2.5, 1.25, 0.625 and 0.3125 wt% crystalline ETR. The diluent was a fully amorphous solid dispersion with equal proportions of ETF, SSF and HPMC-E5 to keep the ETR loading at 25%.

[0109] For each sample of the serial dilution, multiple UV / vis reflectance spectra were obtained. The spectra of the mixtures with 20, 10, 5, 2.5, 1.25 and 0.625 wt% crystalline ETR are shown in Figure 3 as shown in .

[0110] At all measured wavelengths, the total reflection increases with increasing crystallinity. There is a clear correlation between the amount of crystalline ETR (20 to 0.6 wt%) and the reflection observed in each UV / vis spectrum. The amount of crystalline ETR was independently verified on the same samples using offline XRD and Raman spectroscopy.

[0111] also, Figure 4 Overlaid UV / vis spectra of another series of ETR formulations of varying degrees of crystallinity are shown. There is an equally clear correlation between the amount of crystalline ETR (0 to 9.8 wt%) and the reflections observed in each UV / vis spectrum.

[0112] Method 3 - Predictive Modeling of Crystallinity

[0113] To prepare a predictive model for determining crystallinity, the reflectance spectra of each crystalline ETR quantity from Method 2 were first converted to their second derivatives and then processed by standard normal variate (SNV) analysis and Savitzky Golay analysis to generate a moving average of all data points in each spectrum. After these data processing steps to normalize and smooth the spectral data, principal component analysis (PCA) was performed on the data to provide the first principal component (factor 1), which was found to explain approximately 98% of the spectral variance (see Fig. 9 and 10 ). The factor 1 (y-axis) is plotted against the wavelength (x-axis) in the range of 290-400 nm. Fig. 9 Shown is and represents a simplified “spectrum” that best fits the entire data set of samples over the range of crystallinity examined.

[0114] Factor 2 largely explains the remaining 2% of the variance in the dataset ( Fig.10 ). The scatter plot of factor 2 (y-axis) relative to factor 1 (x-axis) is Fig.11 The clustering of samples according to crystallinity (i.e., 2.5% crystallinity samples (squares), 5% crystallinity samples (circles), 10% crystallinity samples (triangles), and 20% crystallinity samples (diamonds)) was found. This indicates that processing the UV / vis spectral data to form a PCA model successfully resolved the spectra, thereby distinguishing samples by crystallinity in the range of 2.5%-20%.

[0115] exist Fig.12 In the example, the crystallinity predicted by factor 1 (y-axis) is plotted against the known (reference) crystallinity level of the sample (x-axis). A high correlation can be seen (R squared value above 0.99). The example shows that processing UV / vis spectra to generate a PCA model, optionally after data normalization and / or smoothing, helps determine the crystallinity of one or more samples by the method of the invention.

[0116] Importantly, without wishing to be bound by any particular theory, the present inventors believe that many other API / carrier combinations will be suitable for such PCA modeling because PCA is an adaptive analysis that can be used to reduce the complexity or dimensionality of spectral data without requiring knowledge of what causes a particular spectral shape or pattern.

[0117] In some cases, the data can be further processed by partial least squares regression (PLSR) to conveniently compare and predict the crystallinity of one or more samples based on their UV / vis spectra, particularly with reference to a "standard curve" formed from values ​​obtained from multiple reference samples of known crystallinity and having the same API and carrier as the subject sample or samples.

[0118] Since the total reflectance and total absorbance of a sample vary with crystallinity, another approach to modeling UV / vis spectral data is to generate and plot the L* values ​​of reference samples with known and varying degrees of crystallinity.

[0119] L* is the lightness value component of L*a*b* according to the "CIELAB color space" defined by the International Commission on Illumination (CIE), where the darkest black is L*=0 and the lightest white is L*=100. A graph of this L* value versus crystallinity is shown in FIG. Figure 5 A clear and linear correlation between crystallinity and L* value is observed, especially above 1% crystallinity.

Claims

1. A method for generating a predictive model for determining the amount of crystallinity of an active pharmaceutical ingredient in an amorphous solid dispersion or solid solution, the method comprising the steps of: (i) subjecting a plurality of reference samples spanning a range of crystallinity of an active pharmaceutical ingredient to UV / vis spectroscopy analysis, wherein the plurality of reference samples are a plurality of amorphous solid dispersions or solid solutions, (ii) measuring the reflectance spectrum and / or the transmittance spectrum of each reference sample, and (iii) processing the spectra collected in step (ii) to generate a predicted crystallinity model.

2. The method according to claim 1, wherein the number of reference samples is 5 or more.

3. The method according to claim 1 or 2, wherein the spectrum is pre-processed before step (iii) to normalize and / or smooth the spectrum.

4. The method of claim 3, wherein the spectrum of the reference sample is processed to derive features related to crystallinity across at least a portion of the crystallinity range.

5. The method of claim 4, wherein the features include: at least a first principal component derived from a principal component analysis of the spectrum, wherein the variance of the crystallinity of the first principal component is linear over the range of crystallinity of the plurality of amorphous solid dispersions or solid solutions; or The lightness value L* in the CIELAB color space is derived from the spectrum.

6. A method for testing a pharmaceutical composition comprising an active pharmaceutical ingredient in an amorphous solid dispersion or solid solution for the crystallinity of the active pharmaceutical ingredient, the method comprising the following steps; (i) subjecting the amorphous solid dispersion or solid solution to UV / vis spectroscopy analysis, (ii) measuring the reflection spectrum and / or the transmission spectrum, (iii) determining the presence or absence of crystallinity of the active pharmaceutical ingredient by comparing the measured reflectance spectrum and / or transmission spectrum with the expected spectrum for a completely amorphous sample, and (iv) determining the amount of crystallinity in the amorphous solid dispersion or solid solution by comparing the observed spectrum to a prediction model generated according to the method of claim 1 when a crystalline active pharmaceutical ingredient is found to be present.

7. The method of claim 6, wherein comparing the observed spectrum to the predictive model comprises processing the observed spectrum in the same manner as the spectra of the plurality of reference samples according to claim 1.

8. The method of claim 6, wherein the amount of crystallinity in the amorphous solid dispersion or solid solution is measured to be 50 wt% and below.

9. The method of claim 8, wherein the amount of crystallinity in the amorphous solid dispersion or solid solution is measured at 1 wt% and above.

10. A method for manufacturing a pharmaceutical composition, the method comprising the following steps: (i) forming an active pharmaceutical ingredient into an amorphous solid dispersion or solid solution, (ii) testing the amorphous solid dispersion or solid solution one or more times for the crystallinity of the active pharmaceutical ingredient by the method of claim 6, and (iii) when the amorphous solid dispersion or solid solution has an amount of crystallinity within an acceptable range, processing the composition into a finished pharmaceutical product.

11. The method according to claim 10, wherein: Forming the active pharmaceutical ingredient into an amorphous solid dispersion or solid solution is performed by extrusion, ball milling or spray drying; and / or Testing the amorphous solid dispersion or solid solution one or more times for the presence or absence of crystallinity is performed in-line.

12. The method of claim 11, wherein the forming is performed by extrusion and the testing is performed at one or more of the active pharmaceutical ingredient input point, upstream of the extrusion point, and the extrusion point.

13. The method of claim 11, wherein the forming is performed by ball milling in a ball mill having one or more clearing points, wherein the testing is performed with the one or more clearing points perpendicular to the axis of motion.

14. The method of claim 11, wherein the forming is performed by spray drying and the testing is performed at one or more of the active pharmaceutical ingredient input point, the atomization point in the drying chamber, or the sedimentation point after atomization.

15. The method according to claim 10, wherein the acceptable range of the crystallinity is 1 wt% or less.

16. The method of claim 11, wherein the active pharmaceutical ingredient input to the screw extruder, ball mill or spray dryer is automatically adjusted when necessary to ensure that the crystallinity is within the acceptable range.

17. The method of claim 11, wherein the speed of the screw extruder, ball mill or spray dryer is automatically adjusted when necessary to ensure that the crystallinity is within the acceptable range.

18. The method of claim 11, wherein the temperature of the extruder barrel, ball mill or spray dryer is automatically adjusted when necessary to ensure that the crystallinity is within the acceptable range.

19. The method of claim 10, wherein the UV / vis reflection and / or transmission is measured continuously.

20. The method according to any one of claims 1, 6 and 10, wherein the reflection spectrum and / or transmission spectrum is measured at a wavelength of 210 to 800 nm.

21. The method of any one of claims 1, 6 and 10, wherein only the reflection spectrum is measured.

22. The method of any one of claims 1, 6 and 10, wherein only the transmission spectrum is measured.

23. The method according to any one of claims 1, 6 and 10, wherein the particle size of the amorphous solid dispersion or solid solution is measured before UV / vis spectroscopy analysis.

24. The method of claim 23, wherein the amorphous solid dispersion or solid solution is sized to match the size of one or more reference samples of known crystallinity, wherein the reference samples match the active pharmaceutical ingredient and carrier of the amorphous solid dispersion or solid solution.

25. The method according to any one of claims 1, 6 and 10, wherein the active pharmaceutical ingredient is a compound having a molecular weight of 2000 g / mol or less.

26. The method of any one of claims 1, 6, and 10, wherein the active pharmaceutical ingredient is at least 95% pure prior to incorporation into the amorphous solid dispersion or solid state solution.

27. The method of any one of claims 1, 6, and 10, wherein the active pharmaceutical ingredient comprises 5 wt% or less water.

28. The method of any one of claims 1, 6, and 10, wherein the active pharmaceutical ingredient is a non-nucleoside reverse transcriptase inhibitor or a non-steroidal anti-inflammatory drug.

29. The method of claim 28, wherein the non-nucleoside reverse transcriptase inhibitor is etravirine and the non-steroidal anti-inflammatory drug is piroxicam.

30. The method of any one of claims 1, 6, and 10, wherein the carrier of the amorphous solid dispersion or solid solution comprises an amorphous polymer.

31. The method of claim 30, wherein the amorphous polymer is one or more of a cellulosic polymer, a vinyl polymer, a polymethacrylate polymer, and a polyalkylene glycol polymer.

32. The method of claim 31, wherein the amorphous polymer is one or more of ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, polymethacrylate, polyalkylene glycol, polyvinyl pyrrolidone, copovidone, vinyl pyrrolidone-vinyl acetate copolymer, and linear random copolymer of N-vinyl-2-pyrrolidone and vinyl acetate.

33. The method of claim 32, wherein the polyalkylene glycol is one or more of the following: polyethylene glycol, a copolymer of polyethylene glycol, polypropylene glycol, poloxamer, and soluplus, wherein the poloxamer is a triblock polymer having a central hydrophobic polypropylene glycol block flanked by two hydrophilic polyethylene glycol blocks, and the soluplus is a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer.

34. The method of any one of claims 1, 6, and 10, wherein the carrier of the amorphous solid dispersion or solid solution comprises 5 wt% or less water.

35. An apparatus for manufacturing a pharmaceutical composition as an amorphous solid dispersion or solid solution according to the method of claim 10, comprising a quality control system for testing the amount of crystallinity of the active pharmaceutical ingredient in the composition by one or more UV / vis spectrometers configured to measure reflection and / or transmission intensity.

36. Apparatus according to claim 35 comprising a screw extruder, a ball mill or a spray dryer, wherein the or each UV / vis spectrometer is located at an in-line measurement point to measure the reflection and / or transmission of the amorphous solid dispersion or solid solution.

37. The apparatus of claim 36 comprising a screw extruder, wherein the UV / vis spectrometer or at least one of the UV / vis spectrometers is configured to measure reflectance and / or intensity at one or more of an active pharmaceutical ingredient input point, upstream of an extrusion point, and an extrusion point.

38. The apparatus of claim 36 comprising a ball mill having one or more transparent points, wherein the UV / vis spectrometer or at least one of the UV / vis spectrometers is configured to measure reflection and / or transmission through the one or more transparent points and perpendicular to the axis of motion.

39. The apparatus of claim 36 comprising a spray dryer, wherein the UV / vis spectrometer or at least one of the UV / vis spectrometers is configured to measure reflection and / or transmission at one or more of an active pharmaceutical ingredient input point, an atomization point in a drying chamber, and a settling point after atomization.

40. Apparatus according to claim 36, wherein the or each UV / vis spectrometer is photonically connected to the or each measurement point by optical fibres.

41. An apparatus according to claim 36, wherein the apparatus is configured to automatically adjust the active pharmaceutical ingredient input to the screw extruder, ball mill or spray dryer in response to online measurements of the or each UV / vis spectrometer when required.

42. Apparatus according to claim 36, wherein the apparatus is configured to automatically adjust the speed of the screw extruder, ball mill or spray dryer when required in response to online measurements of the or each UV / vis spectrometer.

43. Apparatus according to claim 36, wherein the apparatus is configured to automatically adjust the temperature of the screw extruder, ball mill or spray dryer when required in response to online measurements of the or each UV / vis spectrometer.

44. Apparatus according to claim 35, wherein the or each UV / vis spectrometer is configured to measure reflected and / or transmitted intensity in the range 210 to 800 nm.

45. Apparatus according to claim 35, wherein the or each UV / vis spectrometer is configured to measure reflection and / or transmission continuously.

46. ​​The apparatus according to claim 35, for use in manufacturing a pharmaceutical composition according to claim 10 as an amorphous solid dispersion or solid solution.

Images