Method for preparing a solid dosage form

Abstract

The present disclosure relates to polymorphs of ritonavir prepared by novel methods that require less time to prepare the polymorphs, methods for preparing the polymorphs, pharmaceutical compositions containing the polymorphs prepared by the provided methods, and corresponding methods of treatment using the polymorphs prepared by the provided methods.

Description

[Technical Field]

[0001] The present disclosure relates to novel methods for making the crystalline form of ritonavir known as Form III ritonavir, and methods of using the products made by the methods, as well as pharmaceutical compositions containing the products made by the provided methods. [Background technology]

[0002] Ritonavir is known to be useful for inhibiting HIV protease, inhibiting HIV infection, inhibiting cytochrome P450 monooxygenase, and enhancing the pharmacokinetics of compounds metabolized by cytochrome P450 monooxygenase. Ritonavir is particularly effective in inhibiting HIV infection when used alone or in combination with one or more reverse transcriptase inhibitors and / or when used in combination with one or more other HIV protease inhibitors.

[0003] During the development and initial manufacture of ritonavir, only one crystalline form was identified (Bauer, J., et al., Pharm. Res., 2001, 18(6):859-866). However, because ritonavir was not bioavailable in that form, initially marketed oral formulations containing ritonavir contained ritonavir dissolved in a semi-solid, waxy matrix filled into capsules. Approximately two years after the initial market launch of NORVIR®, a second crystalline form of ritonavir was discovered. The presence of this crystalline form in the capsule formulation caused the product to fail regulatory-mandated dissolution specifications. This new form, designated "Form II," was later found to be supersaturated in the hydroalcoholic solution used in the formulation, whereas the originally known form, now designated "Form I," was not. The sudden appearance of the significantly less soluble Form II disrupted the manufacture of the original NORVIR® formulation, severely threatening the drug's supply. Eventually, at great expense, a new formulation of NORVIR® was developed.

[0004] To date, three polymorphs (identical chemical composition) of ritonavir have been reported: Forms I and II are as described in U.S. Pat. No. 7,148,359 ("U.S. Pat. No. 359"), and a third form obtained by Morissette et al. was initially described as "Form V" ritonavir in U.S. Pat. No. 7,205,413 ("U.S. Pat. No. 413") and later as "Form IV" ritonavir in Morissette et al., PNAS, 2003, 100 (5) 2180-2184 ("Morissette 2003"). This form is referred to herein as "Form IV ritonavir."

[0005] Recently, researchers at AbbVie published a preliminary report reporting the discovery of a new anhydrous form of ritonavir, "Form III" (Yao, X., et al. ("Yao 2022")). However, this form appears to have been observed by Kawakami et al. (Molecular Pharmaceutics, 2014, 11(6): p. 1835-1843).

[0006] An overlay of the X-ray powder diffraction (XRPD) pattern of ritonavir Form III published by AbbVie, provided herein, with the XRPD pattern of ritonavir published by Kawakami et al. in 2014 (see Figure 2) indicates that the ritonavir designated by Kawakami et al. as "Form IV" is in fact a mixture of AbbVie's Form III ritonavir ("Yao 2022") and amorphous ritonavir, although Kawakami et al. appear not to have recognized this. Summary of the Invention [Problem to be solved by the invention]

[0007] There is a need for a more consistent and rapid method for producing crystalline Form III ritonavir, which has promising bioavailability. [Means for solving the problem]

[0008] Coincidentally, around the same time as AbbVie's announcement (i.e., "Yao 2022"), the present inventors were also studying ritonavir and simultaneously discovered the same Form III of ritonavir through an improved method. The present disclosure provides a simple thermal method for producing Form III in a shorter time than previously reported methods, and the method can be easily performed on the ground or under reduced gravity.

[0009] In some embodiments of the present disclosure, a method for obtaining Form III of ritonavir is provided, comprising: melting a sample of Form II of ritonavir; and cooling the sample to a first temperature within a nucleation temperature range for a nucleation period to obtain Form III of ritonavir.

[0010] In certain embodiments, the method further includes holding the temperature at a first temperature for a nucleation period; and optionally ramping the sample from the first temperature to a second temperature, wherein the first temperature and the second temperature are within a nucleation temperature range.

[0011] In a further embodiment of the present disclosure, we describe Form III ritonavir prepared by the processes herein.

[0012] In certain embodiments, the resulting Form III ritonavir comprises a mixture of amorphous ritonavir and Form III ritonavir.

[0013] In a further embodiment of the present disclosure, there is provided a pharmaceutical composition comprising Form III ritonavir and one or more pharmaceutically acceptable excipients.

[0014] In a further embodiment of the present disclosure, a method of treating a disease, such as HIV, COVID-19, and / or a disease associated with inhibition of cytochrome P450-3A4, comprises treating a patient in need thereof with a therapeutically effective amount of Form III of ritonavir, such as with a pharmaceutical composition of Form III of ritonavir.

[0015] In one embodiment of the present disclosure, a method for obtaining Form III of ritonavir is provided, comprising the steps of: melting a sample of ritonavir; cooling the sample to a first temperature within a nucleation temperature range for a nucleation period; and obtaining Form III of ritonavir.

[0016] In certain embodiments, the method further includes holding the temperature at a first temperature for a nucleation period; and optionally ramping the sample from the first temperature to a second temperature, wherein the first temperature and the second temperature are within a nucleation temperature range.

[0017] In certain embodiments, the nucleation temperature range is greater than 60°C to about 100°C.

[0018] In certain embodiments, the resulting Form III ritonavir is formed within the nucleation temperature range.

[0019] In certain embodiments, the X-ray powder diffraction pattern of Form III of ritonavir comprises peaks at about 7.9° and about 9.1°. In certain embodiments, the X-ray powder diffraction pattern of Form III of ritonavir further comprises one or more peaks at about 7.5°, about 10.8°, about 13.1°, about 15.0°, about 15.9°, about 17.0°, about 18.2°, about 18.8°, and about 20.1°.

[0020] In certain embodiments, the differential scanning calorimetry thermogram of Form III ritonavir has an endotherm with an onset temperature of about 114°C.

[0021] In certain embodiments, the form of the ritonavir sample that is melted is selected from amorphous ritonavir, ritonavir Form I, ritonavir Form II, or ritonavir Form IV. In certain embodiments, the form of the ritonavir sample that is melted is selected from amorphous ritonavir, ritonavir Form I, or ritonavir Form II. In certain embodiments, the form of the ritonavir sample that is melted is selected from amorphous ritonavir or ritonavir Form I. In certain embodiments, the form of the ritonavir sample that is melted is selected from amorphous ritonavir or ritonavir Form II. In certain embodiments, the form of the ritonavir sample that is melted is ritonavir Form I.

[0022] In certain embodiments, melting comprises increasing the temperature of the sample to a melting temperature of 125°C or greater. In certain embodiments, the melting temperature is between about 125°C and about 128°C.

[0023] In certain embodiments, the melting temperature is maintained above the melting point of ritonavir Form II until the entire sample is melted. In certain embodiments, the melting temperature is maintained above the melting point of ritonavir Form II until no crystalline particles are visible. In certain embodiments, the melting temperature is maintained above the melting point of ritonavir Form II until no seed crystals of Form II are present in the melt.

[0024] In certain embodiments, the melting temperature is held for at least 2 minutes. In certain embodiments, the melting temperature is held for at least 15 minutes. In certain embodiments, the melting temperature is held for between about 15 minutes and about 30 minutes.

[0025] In certain embodiments, the nucleation period is between 1 hour and 48 hours. In certain embodiments, the nucleation period is about 23 hours. In certain embodiments, the nucleation period is about 37 hours.

[0026] In certain embodiments, crystallization of the sample is substantially complete during the nucleation period, hi certain embodiments, the nucleation period is until conversion of Form II ritonavir to Form III ritonavir in the sample is substantially complete.

[0027] In certain embodiments, the methods provided by the present disclosure further comprise the step of cooling the obtained Form III of ritonavir, hi certain embodiments, the obtained Form III of ritonavir is cooled to a temperature below the glass transition temperature of amorphous ritonavir.

[0028] In certain embodiments, the amount of sample thawed is between about 0.5 mg and about 300 mg.

[0029] In certain embodiments, the sample is confirmed to be melted by the absence of crystalline material when observed by hot stage optical microscopy (HSOM).

[0030] In certain embodiments, the crystallization is carried out under reduced gravity conditions.

[0031] In certain embodiments, the reduced gravity conditions occur within a spacecraft orbiting the Earth.

[0032] In another embodiment, there is provided Form III of ritonavir prepared by the methods of the present disclosure.

[0033] In another embodiment, there is provided a pharmaceutical composition comprising III ritonavir in a form prepared by the method of the present disclosure and one or more pharmaceutically acceptable excipients.

[0034] In another embodiment, a method of treating one or more of HIV or COVID-19 comprises administering to a patient in need thereof a pharmaceutically acceptable amount of Form III of ritonavir, provided as prepared by the methods of the present disclosure.

[0035] In another embodiment, a method for inhibiting cytochrome P450-3A4 comprises administering to a patient in need thereof a pharmaceutically acceptable amount of Form III ritonavir, provided as prepared by the methods of the present disclosure.

[0036] These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description and accompanying drawings. [Brief explanation of the drawings]

[0037] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of ritonavir Form III of Example 1f. [Figure 2] Panels A-C show a comparison of XRPD patterns corresponding to Form IV ritonavir (top XRPD pattern) reported by Morissette et al. (Panel A), Kawakami's "Form IV" after heating at 60° C. for 6 and 8 days (Panel B), and Form III ritonavir of the present disclosure (Panel C). The three XRPD patterns are shown with the same scale of the X-axis (°2θ), with a vertical dashed line corresponding to the peaks of Form III ritonavir of the present disclosure, to facilitate comparison of peaks between the various XRPD patterns reported for other forms of ritonavir. [Figure 3] Panels A-B show the XRPD patterns of ritonavir Form III of the present disclosure (top) and Yao et al., 2022. [Figure 4]Figure 4 shows evidence confirming that the material obtained herein is Form III ritonavir. Line A in Figure 4 shows the substantial overlap of two XRPD patterns of Form III ritonavir. Line A is the experimentally obtained XRPD pattern of Form III ritonavir of the present disclosure (Example 1f), and the other is obtained from Line C, which is the index solution of that XRPD pattern including Pawley refinement. The goodness of fit is represented by Line B in Figure 4, which is the difference between the XRPD patterns. The magnitude of the difference is small compared to the magnitude of most of the peaks, indicating a relatively high goodness of fit. Line C in Figure 4 shows all the accepted peaks obtained from the index solution after Pawley refinement. [Figure 5] 1 is a differential scanning calorimetry (DSC) thermogram of ritonavir Form III obtained as described in Example 1f, with an endotherm of approximately 23.62 J / g. [Figure 6A] FIG. 1 is a HSOM image of a Form III ritonavir sample obtained as described in Example 1f, showing an onset of melting at 113.7° C. [Figure 6B] FIG. 1 is a HSOM image of a Form III ritonavir sample obtained as described in Example 1f, showing melting continuity at 115.8° C. FIG. [Figure 6C] FIG. 1 is a HSOM image of a Form III ritonavir sample obtained as described in Example 1f, showing melting continuity at 117.0° C. FIG. [Figure 6D] FIG. 1 is a HSOM image of a Form III ritonavir sample obtained as described in Example 1f, showing complete melting at 117.9° C. [Figure 7] FIG. 1 shows the temperature-gravity (TG) curve of ritonavir Form III obtained as described in Example 1f. [Figure 8] FIG. 1 shows the DVS (dynamic vapor sorption) isotherm of ritonavir Form III obtained as described in Example 1f. [Figure 9A]FIG. 1 shows the Raman spectrum of ritonavir Form III obtained as described in Example 1f, providing the full spectral range. [Figure 9B] FIG. 1 provides a magnified view of the Raman spectrum of ritonavir Form III obtained as described in Example 1f. [Figure 10A] FIG. 16 shows Raman spectra of ritonavir short-term stability results of Form III of Example 1f, providing the full spectral range. [Figure 10B] FIG. 16 is a Raman spectrum of ritonavir Form III short-term stability results of Example 1f, providing a close-up view. [Figure 11A] FIG. 1B is a Raman spectrum of ritonavir Form III during the 5-week stability study described in Example 1c, providing the full spectral range. [Figure 11B] FIG. 1C provides a magnified view of the Raman spectrum of ritonavir Form III during the 5-week stability study described in Example 1c. [Figure 11C] FIG. 1B is a Raman spectrum of ritonavir Form III in the 23-week stability study described in Example 1c, providing the full spectral range. [Figure 11D] FIG. 1C provides a magnified view of the Raman spectrum of ritonavir Form III in the 23-week stability study described in Example 1c. [Figure 12A] FIG. 10 shows HSOM images at 90° C. of Form III ritonavir crystals grown from a supercooled melt when held for 5 hours. [Figure 12B] FIG. 10 shows HSOM images at 85° C. of Form III ritonavir crystals grown from a supercooled melt when held for 5 hours. [Figure 12C] FIG. 10 shows HSOM images at 80° C. of Form III ritonavir crystals grown from a supercooled melt when held for 5 hours. [Figure 12D] FIG. 10 shows HSOM images at 75° C. of Form III ritonavir crystals grown from a supercooled melt when held for 5 hours. [Figure 12E] FIG. 10 shows HSOM images at 70° C. of Form III ritonavir crystals grown from a supercooled melt when held for 5 hours. [Figure 13A] FIG. 1 shows a HSOM image of Form III ritonavir crystals grown at 80° C. from a supercooled melt after 5 hours. [Figure 13B] FIG. 1 shows a HSOM image of Form III ritonavir crystals grown at 80° C. from a supercooled melt after 8 hours. [Figure 14] FIG. 1 shows the temperature profile used to provide Form III ritonavir from a supercooled melt within 23 hours. [Figure 15] FIG. 15 shows the XRPD patterns of Form III ritonavir at 40° C. / 75% relative humidity (RH) on days 30, 60, and 96, with the arrow at day 96 indicating the presence of the Form I peak in the sample. [Figure 16] FIG. 1 shows the XRPD patterns of ritonavir Form III before and after milling. [Figure 17] FIG. 1 shows the XRPD patterns of ritonavir Form III before and after physical compression. [Figure 18] FIG. 1 shows a representative UV / visible spectrum of the solubility of Form III ritonavir in 0.1 N hydrochloric acid after 24 hours. [Figure 19] FIG. 19 shows the solubility standard curve of Form II ritonavir in 0.1 N hydrochloric acid at 247 nm. [Figure 20] FIG. 1 shows the solubility profiles of Form I, Form II, Form III and amorphous ritonavir in 0.1 N hydrochloric acid. [Figure 21] FIG. 1 shows XRPD patterns of samples taken after 12 hours, 24 hours, and 48 hours in a dissolution test of amorphous ritonavir in 0.1 N hydrochloric acid. [Figure 22] FIG. 1 shows the XRPD patterns of samples taken after 12 hours, 24 hours, and 48 hours in a dissolution study of ritonavir Form I in 0.1 N hydrochloric acid. [Figure 23] FIG. 1 shows the XRPD patterns of samples taken after 12 hours, 24 hours, and 48 hours in a dissolution study of ritonavir Form II in 0.1 N hydrochloric acid. [Figure 24] FIG. 1 shows the XRPD patterns of samples taken after 12 hours, 24 hours, and 48 hours in a dissolution study of ritonavir Form III in 0.1 N hydrochloric acid. DETAILED DESCRIPTION OF THE INVENTION

[0038] Many compounds can exist in different crystalline forms (i.e., polymorphs). Individual polymorphs can exhibit different physical, chemical, and spectroscopic properties. For example, certain polymorphs may dissolve more readily in certain solvents, flow more readily, or be more easily compressed than other polymorphs. See, for example, P. DiMartino, et al., J. Thermal Anal., 48:447-458 (1997). In the case of pharmaceuticals, certain forms may be more bioavailable than others, and other forms may be more stable under certain manufacturing, storage, and biological conditions. This is particularly important from a legal perspective, because pharmaceuticals are approved by agencies such as the U.S. Food and Drug Administration (FDA) only if they meet strict purity and performance standards. In fact, regulatory approval of one polymorph of a compound (exhibiting certain solubility and physicochemical properties, including spectroscopic properties) typically does not immediately lead to approval of other polymorphs of the same compound.

[0039] Ritonavir is chemically named 10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-onic acid, 5-thiazolylmethyl ester, [5S-(5R,8R,10R,11R)] and has the following structural formula:

[0040] [ka]

[0041] A variety of spectroscopic and crystallographic techniques are used to characterize solid forms of compounds, such as anhydrates, hydrates, solvates, etc. These methods include X-ray powder diffraction ("XRPD"), single crystal X-ray diffraction, Raman spectroscopy, infrared spectroscopy, solid state NMR spectroscopy, among others.

[0042] Different solid forms of the same compound typically exhibit different thermal properties, such as melting temperatures (melting points). Thermal properties are analyzed by techniques such as hot-stage optical microscopy (HSOM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC), to name a few. These techniques are used to identify, characterize, and distinguish between various solid forms.

[0043] Data obtained from a given technique can be used in multiple ways to characterize a solid form, such as to confirm the presence of a particular polymorph. For example, the entire XRPD pattern output from a diffractometer can be used to characterize a solid form, such as an anhydrous polymorph. A compound is polymorphic if two or more crystal structures exist, each of which is a polymorph of the compound. However, smaller subsets of such data can also be, and usually are, suitable for such characterization. For example, a collection of one or more peaks from such a pattern can be used to distinguish polymorphs. Indeed, in many cases, only a single XRPD peak can be used for such characterization. When a solid form, or a mixture of solid forms herein, is characterized by "one or more peaks" in an XRPD pattern, and such peaks are listed, it is meant that any combination of the listed peaks may be used to characterize the solid form. Furthermore, the presence of other peaks in an XRPD pattern does not negate or limit the identification of a particular polymorph.

[0044] The XRPD pattern is an xy graph with °2θ (diffraction angle) on the x-axis and intensity on the y-axis. This angle (°2θ) depends on the wavelength of the radiation based on the Cu source in this disclosure; for example, the d-spacing is α1 The pattern is calculated using a wavelength of 1.5405929 Å, which is the wavelength (Phys. Rev. A56(6) 4554-4568(1997)). This pattern contains peaks that are used to characterize solid forms. Typically, peaks are displayed and referenced by their position on the x-axis, rather than their peak intensity on the y-axis. This is because peak intensity can vary with instrumental and experimental parameters, such as the preferred orientation of the crystal (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Therefore, intensity is typically not used by those skilled in the art to characterize solid forms.

[0045] Similarly, subsets of spectra from other techniques can be used, alone or in combination with other analytical data, for characterization purposes, hi certain embodiments, DSC measurements are used for such characterization purposes.

[0046] As with any data measurement, powder X-ray diffraction exhibits variability. In addition to variations in peak intensities, there is also variability in the position of peaks on the x-axis. However, this variability can typically be accounted for when reporting peak positions for characterization purposes. Such variability in peak positions on the x-axis stems from several sources. One source is sample preparation. Samples of the same crystalline material prepared under different conditions may produce slightly different diffraction patterns. Factors such as particle size, water content, solvent content, and crystal orientation all affect the X-ray diffraction of a sample. Another source of variability stems from instrument parameters. Different X-ray instruments have different parameters, which can result in slightly different diffraction patterns for the same crystalline material. Similarly, X-ray data processing varies between software packages, which also contributes to variability. These and other sources of variability are known to those skilled in the pharmaceutical sciences.

[0047] Because of this source of variability, when describing X-ray diffraction peaks, it is common to use the word "about" before the peak value in degrees 2θ. This word indicates 2θ data within 0.1° or 0.2° of the described peak value, depending on the context. All powder X-ray diffraction peaks cited herein are reported at 2θ with a variability on the order of 0.2° and are intended to be reported with such variability whenever disclosed herein, regardless of whether the word "about" is present.

[0048] Variability also exists in thermal measurements such as DSC and can indicate sample purity. In certain embodiments, melting point, DSC, and hot stage microscopy data are used alone or in combination with techniques such as X-ray powder diffraction, Raman spectroscopy, infrared spectroscopy, or a combination thereof to characterize the solid form. For DSC, typical measurement variability is on the order of 1°C.

[0049] When characterizing or identifying solid forms, additional methods may be useful in analyzing solvates or hydrates, since these solid forms are chemical entities distinct from their anhydrous counterparts. Techniques such as solution NMR, thermogravimetry, and elemental analysis are useful in characterizing such solid forms.

[0050] To the best of the inventors' knowledge, four polymorphs of ritonavir (having identical chemical composition) have been reported. Forms I and II are as described in US 359 (incorporated herein by reference). Form III is as described in Yao 2022 (incorporated herein by reference) (see XRPD pattern in Figure 1, top row). And, "Form IV" of ritonavir was published in Morissette et al. PNAS 2003 (incorporated herein by reference) (see Figure 4A), which was later referred to as "Form V" ritonavir in US 413 (incorporated herein by reference) (see Figure 16). For clarity, this form is referred to herein as "Form IV ritonavir." The currently obtained crystalline form corresponds to Form III ritonavir described in Yao 2022, as confirmed, for example, by comparison of the X-ray diffraction patterns shown in Figures 1-3 below.

[0051] As described in U.S. Pat. No. 413, various other solvates (i.e., which are not polymorphs of ritonavir due to different chemical compositions) have also been reported but are not discussed herein, including a formamide solvate designated "ritonavir(III)" and a partially desolvated formamide solvate "ritonavir(IV)."

[0052] Figure 1 shows the X-ray diffraction pattern for Form III of ritonavir of the present disclosure. Figure 2 shows a comparison of Form IV of ritonavir (top diffraction pattern), Kawakami's material (middle XRPD pattern) (XRPD patterns a and b), and Form III of ritonavir of the present disclosure (bottom XRPD pattern). For ease of comparison, the XRPD patterns are shown with the x-axis at the same scale of °2θ. The dotted line extending from the diffraction pattern of Form III of ritonavir of the present disclosure facilitates comparison of peaks in the multiple diffraction patterns in Figure 2. As can be seen, there is significant overlap in peak positions between Form III of ritonavir and Kawakami's XRPD patterns (a) and (b). In comparison, there is poor correspondence in the diffraction pattern peaks between Form IV of ritonavir (Morissette et al.) and either of Kawakami's two XRPD patterns or Form III of ritonavir of the present disclosure. It is therefore understood that Kawakami did not reproduce Form IV of Morissette et al., but instead created what is now known as Form III.

[0053] 3 shows an overlay of the XRPD pattern of Form III ritonavir prepared herein (top) with the XRPD pattern of newly reported Form III ritonavir from AbbVie ("Yao 2022"). The dotted line indicates a very good match between these patterns, confirming that AbbVie's Form III ritonavir and the Form III ritonavir of the present disclosure are the same polymorph.

[0054] Table 1 below shows the observed peaks found in the X-ray powder diffraction pattern of ritonavir Form III, which corresponds to the XRPD pattern shown in FIG.

[0055] [Table 1]

[0056] Form III of ritonavir is easily distinguishable from Form I and Form II of ritonavir. The peaks in "US 359" are reported to have a 2θ variation of ±0.1°. For example, a peak at 8.33° is reported for Form I of ritonavir. This means that a peak may appear at a 2θ value between 8.23° and 8.43°. In comparison, the closest peak to Form III of ritonavir of the present disclosure is approximately 7.9°, with a 2θ variation of ±0.2°. This means that a peak may appear between 7.8° and 8.1°. Thus, the 7.9° peak distinguishes Form III of ritonavir from Form I of ritonavir. The closest peak to approximately 7.9° in Form II of ritonavir is 8.6°, which is further away than the peak for Form I. Thus, the peak at about 7.9° for Form III ritonavir similarly distinguishes Form III ritonavir from Form II ritonavir.

[0057] In addition to the aforementioned Forms I, II, and III, there is another known ritonavir polymorph, designated herein as Form IV ritonavir (described by Morissette et al.). Therefore, peak selection should also be considered when comparing to this polymorph. Figure 4A of Morissette 2003 (corresponding to Figure 16A of US 413) shows the XRPD pattern and peak table corresponding to Form IV ritonavir. This XRPD pattern contains six peaks below about 12.0°: 3.37°, 6.39°, 6.79°, 7.609°, 9.912°, and 11.25°. While peak variation is not specified in either Morissette 2003 or US 413, a 2θ variation of ±0.2° is typical and will be assumed here. Using a 2θ variation of ±0.2°, the peak for Form III ritonavir at approximately 7.9° overlaps with the peak for Form IV ritonavir at 7.609°. However, there is no overlap between the peak for Form III ritonavir at approximately 9.1° and the closest peak for Form IV ritonavir at 9.912°. Thus, the peak at approximately 9.1° distinguishes Form III ritonavir from Form IV ritonavir. The combined peaks for Form III ritonavir at approximately 7.9° and approximately 9.1° distinguish Form III ritonavir from other polymorphs of ritonavir (Form I, Form II, and Form IV ritonavir) and are suitable for characterizing Form III ritonavir.

[0058] In certain embodiments, Form III of ritonavir is characterized by an X-ray powder diffraction pattern comprising peaks at about 7.9° and about 9.1°, and optionally one or more peaks selected from about 7.5°, about 10.8°, about 13.1°, about 15.0°, about 15.9°, about 17.0°, about 18.2°, about 18.8°, and about 20.1°. In certain embodiments, Form III of ritonavir is characterized by an X-ray powder diffraction pattern comprising peaks at about 7.9° and about 9.1°, and two or more peaks selected from about 7.5°, about 10.8°, about 13.1°, about 15.0°, about 15.9°, about 17.0°, about 18.2°, about 18.8°, and about 20.1°. In certain embodiments, Form III of ritonavir is characterized by a powder X-ray diffraction pattern comprising peaks at about 7.9° and about 9.1°, and three or more peaks selected from about 7.5°, about 10.8°, about 13.1°, about 15.0°, about 15.9°, about 17.0°, about 18.2°, about 18.8°, and about 20.1°. The use of the term "about" with respect to peaks in the diffraction patterns depicted herein includes ±0.2° as stated above. For example, the peak at about 7.9° encompasses peaks from 8.1° to 7.7°. The use of the term "about" in other contexts herein includes a range of ±2% of the stated value.

[0059] Form III ritonavir was indexed with the solution shown in Figure 4. This solution included a Pauly refinement. Indexing an XRPD pattern is a computational method that searches for a set of crystallographic space group and unit cell parameters to match the observed Bragg angles in a powder pattern. If indexing is successful and all observed Bragg peaks can be resolved into the indexed solution, the XRPD pattern is likely to represent a single crystalline phase.

[0060] The powder X-ray diffraction pattern of Form III ritonavir prepared herein gave the appropriate indexing solution, as shown in Figure 4, and the cell parameters shown in Table 2 below. The unit cell parameters calculated based on the experimental diffraction pattern of Form III ritonavir are identical, within experimental error, to the parameters characterizing Form III published by "Yao 2022."

[0061] [Table 2]

[0062] Ritonavir Form III was also characterized by three thermal techniques: DSC, HSOM, and TGA. The DSC curve is shown in Figure 5. The sample had an endothermic onset temperature of approximately 114°C, indicating the onset of melting, with a peak at approximately 118°C. HSOM results for ritonavir Form III also showed an onset of melting temperature of approximately 114°C. Images of the onset and completion of melting are shown in Figures 6A-6D, which provide images taken at 115.8°C, 117.0°C, and 117.9°C. The sample was completely melted by approximately 118°C and did not recrystallize upon cooling to 26.2°C.

[0063] In certain embodiments, Form III of ritonavir is characterized by an endotherm of about 114° C., e.g., 113.5° C. to 114.5° C. Optionally, such characterization can be performed in combination with other characterizing analytical measurements, such as X-ray powder diffraction and / or Raman spectroscopy.

[0064] TG (thermogravimetric) analysis of Form III ritonavir provided herein did not show any appreciable weight loss (Figure 7). DVS (dynamic vapor sorption) analysis of Form III ritonavir provided herein, shown in Figure 8, confirmed that Form III ritonavir is not hygroscopic (negligible weight gain), which proceeded inversely during the desorption process. No hysteresis was observed.

[0065] Some crystals produced in HSOM (hot stage optical microscopy) experiments (microcrystallization) were subsequently analyzed by Raman microscopy. At least five spectra were collected for each sample. In some cases, more than one morphology was found for each sample. Table 3 below summarizes the Raman findings.

[0066] [Table 3]

[0067] Similarly, the Raman spectrum was obtained from Example 1f. Figures 9A and 9B show the spectrum of ritonavir Form III from the macro experiment, along with a representative Form III spectrum from the microcrystallization experiment (Example 1c). Each spectrum is the average of 10 separate spectra collected for each sample. The spectra of ritonavir Form III are consistent.

[0068] Several stability analyses were performed on Form III ritonavir. Short-term thermal stability experiments were performed by sequentially holding the material of Example 1f at 50°C for 15 minutes, 70°C for 15 minutes, and 90°C for 15 minutes. After exposure to each temperature, the sample was analyzed by Raman microscopy. In all cases, the material remained Form III ritonavir. Figure 10 compares the short-term thermal stability results with the reference spectrum in Figure 9.

[0069] Additionally, long-term stability studies were performed. Ritonavir Form III from Example 1c was reanalyzed after storage under ambient conditions for 5 weeks up to 23 weeks. The Raman results are shown in Figure 11, and the Ritonavir Form III samples remained unchanged.

[0070] Under stress conditions (40°C / 75% RH), conversion of Form III ritonavir to Form I ritonavir was detected in 60 days (Figure 15). In contrast, amorphous ritonavir converted to Form I within 30 days (Table 4).

[0071] [Table 4]

[0072] (stability study) A sample of Form III ritonavir was manually ground using a mortar and pestle for five cycles of 2 minutes each (total 10 minutes). XRPD analysis of the finished product showed it to be amorphous with traces of Form III (Figure 16). The amorphous material remained unchanged after grinding. When Form I was used, a mixture of amorphous and Form I was obtained, and when Form II was used, a mixture of amorphous and Form II was obtained.

[0073] A sample of Form III ritonavir was compressed at 700 lbs. XRPD analysis showed no change before and after compression (Figure 17). Similar results were obtained using amorphous or Form I material.

[0074] (Solubility study) The solubilities of Form I, Form II, Form III, and amorphous ritonavir in 0.1 N hydrochloric acid were measured using UV / visible spectroscopy. A representative UV / visible spectrum (with an absorbance maximum at 247 nm) for the solubility of Form III in 0.1 N hydrochloric acid is shown in Figure 18. A standard curve for Form II (Figure 19) yielded a linear regression correlation coefficient of 0.99 or greater and was used to determine the concentration of dissolved material at each time point for each studied form.

[0075] The solubility profiles of Form I, Form II, Form III, and amorphous ritonavir are shown in Figure 20. The profiles demonstrate that equilibrium solubility was reached for all materials evaluated by the end of the experiment (48 hours). Evaluation of the recovered solids by powder X-ray diffraction (XRPD) after 12, 24, and 48 hours for each material indicated that no form conversion occurred during the solubility experiment (Figures 21-24). The solubility results are shown in Table 5. Form III exhibited superior solubility compared to Form I and Form II, while the amorphous form exhibited poor solubility in the aqueous media studied.

[0076] [Table 5]

[0077] 4.1.1 Preparation of Ritonavir Form III In certain embodiments of the disclosed methods, Form III of ritonavir is prepared by melting a sample of ritonavir and cooling the sample to a first temperature within the nucleation temperature range for a nucleation period, thereby obtaining Form III of ritonavir. In these embodiments, Form III of ritonavir is formed at any stage of the method where the sample is within the nucleation temperature range, including during the initial cooling step. In additional embodiments, the method further comprises holding the sample at one or more additional temperatures within the nucleation temperature range. In certain embodiments, the nucleation temperature range is from about 61°C to about 100°C.

[0078] In certain embodiments, the thawed ritonavir sample is not particularly limited and is selected from any known form of ritonavir. In certain embodiments, the ritonavir sample is anhydrous. In certain embodiments, the anhydrous ritonavir is selected from one or more of amorphous ritonavir, ritonavir form I, ritonavir form II, and ritonavir form IV.

[0079] In certain embodiments, the melting step comprises holding the sample at a melting temperature, wherein the melting temperature is equal to or greater than the melting temperature of the highest melting form of ritonavir comprising the sample and less than the decomposition temperature of ritonavir. In certain embodiments, the melting temperature is at least 1°C higher than the melting temperature of the highest melting form of ritonavir comprising the sample. In certain embodiments, the melting temperature is less than about 200°C. In certain embodiments, the melting temperature is less than about 150°C. In certain embodiments, the melting temperature is less than about 130°C.

[0080] In certain embodiments, the highest melting form of ritonavir in the sample is Form I ritonavir, which has a melting point of 122° C. In these particular embodiments, the melting temperature is between about 122° C. and 128° C. In further embodiments, the melting temperature is selected from at least one of 122° C., 123° C., 124° C., 125° C., 126° C., 127° C., and 128° C.

[0081] In certain embodiments, the highest melting form of ritonavir in the sample is Form II ritonavir, which has a melting point of about 125° C. In these particular embodiments, the melting temperature is greater than about 125° C., e.g., between 125° C. and 128° C. In further embodiments, the melting temperature is selected from at least one of 125° C., 126° C., 127° C., and 128° C.

[0082] In certain embodiments, the highest melting form of ritonavir in the sample is Form IV, which has a melting point of 101° C. In certain of these embodiments, the melting temperature is greater than about 125° C., e.g., between 125° C. and 128° C.

[0083] In certain embodiments, the melting temperature is maintained until the sample is completely melted, i.e., until no solid or crystalline particles, such as seed crystals, remain, e.g., until no solid or crystalline particles of ritonavir Form I, ritonavir Form II, or ritonavir Form IV are visible. Confirmation that the sample is completely melted is accomplished by techniques known in the art, including optical microscopy, such as polarized optical microscopy, as exemplified herein.

[0084] In certain embodiments, the melting step comprises holding a sample of Form II ritonavir at a melting temperature, wherein the melting temperature is higher than the melting point of Form II ritonavir. In certain embodiments, the melting temperature is about 125.0°C or higher, e.g., about 125.5°C or higher, about 126.5°C or higher, about 127.0°C or higher, about 127.5°C or higher, about 128.0°C or higher, about 128.5°C or higher, about 129.0°C or higher, about 129.5°C or higher, about 130.0°C or higher, about 130.5°C or higher, or about 131.0°C or higher, so long as thermal decomposition of ritonavir is not observed. In certain embodiments, the melting temperature is in a range defined by any two of the foregoing temperatures, e.g., about 125.0°C to about 131.0°C, or about 128°C to about 131.

[0085] In certain embodiments, the sample of Form II ritonavir is 0.1 to 10 mg. In further embodiments, the sample is 0.3 to 0.7 mg. In further embodiments, the sample is 0.5 mg.

[0086] In certain embodiments, the sample of Form II ritonavir is between 10 and 50 mg. In certain embodiments, the sample of Form II ritonavir is between 50 and 100 mg. In certain embodiments, the sample of Form II ritonavir is between 100 and 200 mg. In certain of these embodiments, the sample is between 120 and 170 mg, e.g., 150 mg.

[0087] In certain embodiments of the provided methods, the melting step involves raising the temperature to the melting temperature and holding the melting temperature for a period of time (e.g., a period of time sufficient to ensure that the sample has melted), which period of time depends on the form of ritonavir and the size of the sample being melted.

[0088] In certain embodiments of the provided methods, the melting temperature is held for at least 1 minute. In further embodiments, the melting temperature is held for at least 2 minutes. In certain of these embodiments, the sample of ritonavir is 0.1 to 10 mg. In further embodiments, the sample is 0.3 to 0.7 mg. In further of these embodiments, the sample is about 0.5 mg (e.g., 0.4 to 0.6 mg). In certain of these embodiments, the sample is Form II ritonavir.

[0089] In certain embodiments of the provided methods, the melting temperature is maintained for at least 10 minutes. In further embodiments, the melting temperature is maintained for at least 15 minutes. In certain of these embodiments, the ritonavir sample is 100-300 mg. In further embodiments, the sample is 120-170 mg. In further of these embodiments, the sample is 150 mg (e.g., 140-160 mg). In certain of these embodiments, the sample is Form II ritonavir.

[0090] In certain embodiments, when melting, the temperature of the Form II sample can be heated to a temperature greater than 125° C., such as between 125° C. and about 128° C. In certain embodiments, melting is performed to remove all signs of Form II crystals, including seed crystals.

[0091] In embodiments of the methods described herein, heating to such temperatures can be performed for various lengths of time to achieve such melting, including, for example, at least 2 minutes, at least 15 minutes, and / or between about 15 and 30 minutes. Melting can be visually confirmed using HSOM.

[0092] In certain embodiments, the nucleation and growth profile of Form III ritonavir was qualitatively determined from HSOM microcrystallization experiments. The images shown in Figure 12 compare the relative concentrations of crystals within the supercooled melt upon incubation for 5 hours at each of the indicated temperatures. Under these conditions, no nucleation occurred at 100°C (not shown). A minimum concentration of crystals was evident at both 90°C and 70°C, indicating that nucleation and / or growth was slow at both conditions. The highest crystallization concentration under these conditions was observed at 80°C.

[0093] In certain embodiments of the provided methods, the method comprises melting a sample, then cooling the sample to a first temperature within the nucleation temperature range, and holding the sample at one or more temperatures within the nucleation temperature range for a time sufficient to obtain Form III ritonavir. In certain embodiments, the method further comprises, without limitation, ramping the sample temperature to one or more subsequent temperatures within the nucleation temperature range. Generally, the subsequent temperatures (i.e., second, third, fourth, etc.) can be higher or lower than the preceding temperatures, provided that all temperatures are within the nucleation temperature range. For example, in some embodiments, the method comprises ramping the sample from the first temperature to a second temperature within the nucleation temperature range. In certain embodiments, the second temperature is higher than the first temperature. In some embodiments, the second temperature is lower than the first temperature.

[0094] In certain embodiments, the nucleation temperature range is a temperature range in which crystallization of a molten sample is observed within about 5 hours, e.g., within about 3 hours, within about 2 hours, within about 1 hour, within about 50 minutes, within about 40 minutes, within about 30 minutes, within about 25 minutes, within about 20 minutes, within about 15 minutes, within about 8 minutes, or within about 5 minutes.

[0095] In certain embodiments, the nucleation temperature is a temperature range at which crystallization of a molten sample is complete within about 40 hours, about 37 hours, about 35 hours, about 30 hours, about 25 hours, about 23 hours, about 20 hours, about 15 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour.

[0096] In embodiments of the methods provided herein, the nucleation temperature range is from about 60°C to about 100°C. In certain embodiments, the nucleation temperature range is selected from about 61°C to about 100°C. In certain embodiments, the nucleation temperature range is from about 70°C to a temperature selected from 80°C, 81°C, 82°C, 83°C, 84°C, and 85°C. In certain embodiments, the nucleation temperature range is from about 70°C to about 85°C. In certain embodiments, the nucleation temperature range is from 60°C to 100°C. In certain embodiments, the nucleation temperature range is from 65°C to 100°C. In certain embodiments, the nucleation temperature range is from 70°C to 100°C. In certain embodiments, the nucleation temperature range is from 75°C to 100°C. In certain embodiments, the nucleation temperature range is from 80°C to 100°C. In certain embodiments, the nucleation temperature range is from 85°C to 100°C. In certain embodiments, the nucleation temperature range is from 90°C to 100°C. In certain embodiments, the nucleation temperature range is 60°C to 95°C. In certain embodiments, the nucleation temperature range is 60°C to 90°C. In certain embodiments, the nucleation temperature range is 60°C to 85°C. In certain embodiments, the nucleation temperature range is 60°C to 80°C. In certain embodiments, the nucleation temperature range is 60°C to 75°C. In certain embodiments, the nucleation temperature range is 60°C to 70°C. In certain embodiments, the nucleation temperature range is 60°C to 65°C. In certain embodiments, the nucleation temperature range is 65°C to 95°C. In certain embodiments, the nucleation temperature range is 70°C to 90°C. In certain embodiments, the nucleation temperature range is 75°C to 85°C. In certain embodiments, the nucleation temperature is 76°C, 77°C, 78°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C, or 85°C. In certain embodiments, the nucleation temperature is 76°C. In certain embodiments, the nucleation temperature is 77°C. In certain embodiments, the nucleation temperature is 78°C. In certain embodiments, the nucleation temperature is 79°C. In certain embodiments, the nucleation temperature is 80°C. In certain embodiments, the nucleation temperature is 81°C. In certain embodiments, the nucleation temperature is 82°C. In certain embodiments, the nucleation temperature is 83°C.In certain embodiments, the nucleation temperature is 84° C. In certain embodiments, the nucleation temperature is 85° C.

[0097] In certain embodiments, the first or subsequent temperature within the nucleation temperature range is selected from 61° C., 62° C., 63° C., 64° C., 65° C., 66° C., 67° C., 68° C., 69° C., and 70° C., 80° C., 81° C., 82° C., 83° C., 84° C., 85° C., 86° C., 87° C., 88° C., 89° C., 90° C., 91° C., 92° C., 93° C., 94° C., 95° C., 96° C., 97° C., 98° C., 99° C., and 100° C. In certain embodiments, the first or subsequent temperature within the nucleation temperature range is selected from 80° C., 81° C., 82° C., 83° C., 84° C., 85° C., 86° C., 87° C., 88° C., 89° C., and 90° C. In certain embodiments, the first or subsequent temperature within the nucleation temperature range is selected from 70° C., 71° C., 72° C., 73° C., 74° C., 75° C., 76° C., 77° C., 78° C., 79° C., 80° C., 81° C., 82° C., 83° C., 84° C., 85° C., 86° C., 87° C., 88° C., 89° C., and 90° C. In certain embodiments, the first or subsequent temperature within the nucleation temperature range is selected from 70° C., 71° C., 72° C., 73° C., 74° C., 75° C., 76° C., 77° C., 78° C., 79° C., 80° C., 81° C., 82° C., 83° C., 84° C., and 85° C.

[0098] In certain embodiments, the sample is held within the nucleation temperature range until it crystallizes. In certain embodiments, the time the sample is held within the nucleation temperature range is the nucleation period. In certain embodiments, the nucleation period is about 40 hours, up to about 37 hours, up to about 35 hours, up to about 30 hours, up to about 25 hours, up to about 23 hours, up to about 20 hours, up to about 15 hours, up to about 10 hours, up to about 9 hours, up to about 8 hours, about 7 hours, up to about 6 hours, up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2 hours, or up to about 1 hour. In additional embodiments, the nucleation temperature range is between about 70°C and 85°C, or between about 70°C and about 80°C. In certain embodiments, the nucleation period is between 1 hour and 48 hours, including up to about 37 hours, up to about 23 hours, or less. In some embodiments, the melted sample is between 0.5 mg and 300 mg, although larger amounts of sample may be used.

[0099] In certain embodiments, after the nucleation period, the sample is held at a recovery temperature. In certain embodiments, the recovery temperature is below the glass transition temperature of amorphous ritonavir. In certain embodiments, the recovery temperature is below 42°C.

[0100] In certain embodiments, transitions between temperatures, such as from ambient temperature to the melting temperature, from the melting temperature to the first temperature, from the first temperature to the second temperature, or from any temperature within the nucleation temperature range to the recovery temperature, include, but are not limited to, temperature ramp rates of 20°C / min, 15°C / min, 10°C / min, 8°C / min, 6°C / min, 4°C / min, and 2°C / min.

[0101] In certain embodiments, the methods of the present disclosure are performed under standard gravity conditions on Earth. In alternative embodiments, the methods of the present disclosure are performed under reduced gravity conditions, such as those found in Earth orbit within a satellite.

[0102] Figure 13 compares the crystal concentrations after 5 and 8 hours in the same supercooled melt when held at ideal temperature, providing a visual representation of the relative crystallization rates achieved. Additional HSOM microcrystallization experiments determined that (1) initially nucleating Form III at a lower temperature before incubating at a slightly higher temperature did not increase the overall rate of crystallization, while (2) the rate of quenching from the melt to the incubation temperature did affect the nucleation rate.

[0103] Based on general rules of thumb, guidelines from previously studied systems, and measured glass transition temperatures for amorphous ritonavir, Yao 2022 assumes that the maximum nucleation rate from the melt can only be achieved within a narrow temperature range between 60°C and 70°C. Therefore, Yao 2022 initially nucleated Form III ritonavir at 60°C for two days, then continued growth at 90°C for an additional two days. However, based on the empirical methodology developed herein, it was determined that these two temperatures were not optimal for both the nucleation and continued growth of Form III ritonavir from the supercooled melt. Rather, 80°C was identified as the superior nucleation and holding temperature. Using the conditions shown in Figure 14, Form III ritonavir nucleated from the melt within less than 20 minutes, and in at least one instance, nucleation occurred in 7 minutes and 35 seconds on the microscale and nucleated and fully crystallized within 23 hours on the macroscale.

[0104] With respect to Form III ritonavir produced by the methods of the present disclosure, whether produced according to the present disclosure or otherwise, the present disclosure further provides pharmaceutical compositions of Form III ritonavir, which pharmaceutical compositions further comprise one or more pharmaceutically acceptable excipients.The present disclosure further provides methods of treating HIV, COVID-19, or any condition treated by inhibiting cytochrome P450-3A4, comprising administering to a patient in need thereof a therapeutically effective amount of Form III ritonavir, such as the pharmaceutical composition.

[0105] 4.1.2 Pharmaceutical Compositions and Dosage Forms The pharmaceutical compositions and dosage forms of the present disclosure typically comprise ritonavir Form III prepared by the method of the present disclosure, in combination with one or more pharmaceutically acceptable excipients, and optionally one or more additional pharmacologically active compounds.Examples of additional pharmacologically active compounds include, but are not limited to, PIs, NRTIs, and NNRTIs as disclosed herein.Other additional pharmacologically active compounds include, but are not limited to, immunosuppressants, chemotherapeutic agents, antifungal agents, and antibiotics.

[0106] In certain embodiments, the single unit dosage forms of the present disclosure are suitable for oral administration, transmucosal administration (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral administration (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient. Examples of dosage forms include, but are not limited to, tablets; caplets; capsules such as hard gelatin capsules, HPMC capsules, starch capsules, and soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or transmucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

[0107] The composition, shape, and type of dosage form of the present disclosure typically vary depending on its use. For example, a dosage form suitable for transmucosal administration may contain a smaller amount of active ingredient than an oral dosage form used to treat the same indication. This aspect of the present disclosure will be readily apparent to those skilled in the art. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ed., Mack Publishing, Easton Pa. (1990).

[0108] Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including, but not limited to, the manner in which the dosage form will be administered to a patient. For example, an oral dosage form such as a tablet may contain excipients that are not suitable for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredient in the dosage form. For example, the degradation of certain active ingredients may be accelerated by exposure to certain excipients, such as lactose, or to water. Active ingredients containing primary or secondary amines are particularly susceptible to such accelerated degradation. Consequently, the present disclosure encompasses pharmaceutical compositions and dosage forms that contain little, if any, lactose or other mono- or disaccharides. As used herein, the term "lactose-free" means that if lactose is present, the amount is insufficient to substantially increase the decomposition rate of the active ingredient.

[0109] The lactose-free compositions of the present disclosure can include excipients well known in the art and described, for example, in United States Pharmacopoeia (USP) 25-NF20 (2002). Generally, lactose-free compositions include an active ingredient, a binder / filler, and a lubricant in pharmaceutically compatible and acceptable amounts. A preferred lactose-free dosage form includes the active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0110] Because water can accelerate the decomposition of some compounds, the present disclosure also encompasses anhydrous pharmaceutical compositions and dosage forms containing active ingredients. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical field as a means of simulating long-term storage to determine properties such as shelf life or stability over time of a formulation. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-380. Water and heat accelerate the decomposition of certain compounds. Therefore, the effect of moisture on a formulation is very important, since moisture and / or humidity are commonly encountered during the manufacturing, handling, packaging, storage, transportation, and use of formulations.

[0111] Anhydrous pharmaceutical compositions and dosage forms of the present disclosure can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage.

[0112] Anhydrous pharmaceutical compositions should be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions are preferably packaged using materials known to prevent exposure to water so that they can be included in suitable prescription kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials) with or without desiccants, blister packs, and strip packs.

[0113] The present disclosure further encompasses pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate at which an active ingredient decomposes. These compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0114] Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form can vary depending on factors such as, but not limited to, the route by which it is to be administered to patients. However, typical dosage forms of the present disclosure contain ritonavir in an amount of from about 50 mg to about 1000 mg, preferably from about 75 mg to about 750 mg, and most preferably from about 100 mg to about 500 mg.

[0115] Enumerated Embodiments 1. Thawing a sample of ritonavir; cooling the sample to a first temperature within the nucleation temperature range for a nucleation period; obtaining ritonavir form III; 2. A process for obtaining ritonavir form III, comprising: 2. maintaining the temperature at the first temperature for a nucleation period; Optionally, ramping the sample from a first temperature to a second temperature; 2. The method of claim 1, further comprising: 3. The method of embodiment 1 or 2, wherein the nucleation temperature range is from greater than 60°C to about 100°C, such as from 70°C to 90°C, or from 75°C to 85°C, including when the nucleation temperature range is about 80°C. 4. The method of any of embodiments 1 to 3, wherein the X-ray powder diffraction pattern of Form III ritonavir comprises peaks at about 7.9° and about 9.1° 2θ. 5. The X-ray powder diffraction pattern of ritonavir Form III is: (a) one or more peaks at 2θ of about 7.5°, about 10.8°, about 13.1°, about 15.0°, about 15.9°, about 17.0°, about 18.2°, about 18.8°, and about 20.1°; (b) peaks at 2θ of about 7.90°, about 13.06°, about 14.96°, about 18.23°, about 18.77°, and about 20.94°; or (c) Peaks at 2θ of approximately 7.90°, approximately 13.06°, approximately 14.96°, approximately 15.17°, approximately 15.91°, approximately 18.23°, approximately 18.77°, approximately 19.70°, and approximately 20.94° 5. The method of embodiment 4, further comprising: 6. The method of any one of embodiments 1 to 5, wherein the differential scanning calorimetry thermogram of Form III ritonavir has an endotherm with an onset temperature of about 114°C. 7. The method of any of embodiments 1 to 6, wherein the form of the ritonavir sample that is thawed is selected from amorphous ritonavir, ritonavir Form I, ritonavir Form II, or ritonavir Form IV. 8. The method of any one of embodiments 1 to 7, wherein the form of the ritonavir sample that is thawed is Form II ritonavir. 9. The method of any one of embodiments 1 to 8, wherein the melting step comprises increasing the temperature of the sample to a melting temperature of 125°C or higher. 10. The method of embodiment 9, wherein the melting temperature is from about 125°C to about 128°C. 11. The method of embodiment 9 or 10, wherein the melting temperature is higher than the melting point of ritonavir Form II and is maintained until the entire sample is melted. 12. The method of embodiment 9 or 10, wherein the melting temperature is above the melting point of ritonavir Form II and is maintained until no crystalline particles are visible. 13. The method of any of embodiments 9 to 12, wherein the melting temperature is above the melting point of ritonavir Form II and is maintained until no seed crystals of Form II are present in the melt. 14. The method of any of embodiments 9 to 13, wherein the melting temperature is maintained for at least 2 minutes. 15. The method of embodiment 14, wherein the melting temperature is maintained for at least 15 minutes. 16. The method of embodiment 15, wherein the melting temperature is maintained for between about 15 minutes and about 30 minutes. 17. The method of any one of embodiments 1 to 16, wherein the nucleation temperature range is from about 70°C to about 85°C. 18. The method of embodiment 17, wherein the first nucleation temperature is about 80°C. 19. The method of any one of embodiments 1 to 18, wherein the nucleation period is between 1 hour and 48 hours, for example between 1 hour and 23 hours. 20. The method of embodiment 19, wherein the nucleation period is about 23 hours. 21. The method of embodiment 19, wherein the nucleation period is about 37 hours. 22. The method of any one of embodiments 1 to 21, wherein the obtained Form III ritonavir comprises a mixture of amorphous ritonavir and Form III ritonavir. 23. The method of any one of embodiments 1 to 22, wherein crystallization of the sample is substantially complete during the nucleation period. 24. The method of any one of embodiments 1 to 23, further comprising cooling the obtained Form III ritonavir. 25. The method of embodiment 24, wherein the resulting Form III ritonavir is cooled to a temperature below the glass transition temperature of amorphous ritonavir. 26. The method of any one of embodiments 1 to 25, wherein the resulting Form III ritonavir is formed within a nucleation temperature range. 27. The method of any of embodiments 1 to 26, wherein the amount of ritonavir in the sample to be dissolved is between about 0.5 mg and about 5000 mg, for example, between about 0.5 mg and about 2000 mg, between about 0.5 mg and about 1000 mg, between about 0.5 mg and about 700 mg, and between about 0.5 mg and about 300 mg. 28. The method of any one of embodiments 1 to 27, wherein the melting step is completed when no crystalline material is present as observed by HSOM. 29. The method of any one of embodiments 1 to 28, wherein the nucleation period is carried out under reduced gravity conditions. 30. The method of embodiment 29, wherein the reduced gravity conditions are generated in a spacecraft in orbit around the Earth. 31. Ritonavir Form III, prepared by the method of any of embodiments 1 to 30. 32. A pharmaceutical composition comprising ritonavir Form III as described in embodiment 31 and one or more pharmaceutically acceptable excipients. 33. A pharmaceutical composition comprising Form III ritonavir as described in embodiment 31, one or more additional pharmaceutically active ingredients, and one or more pharmaceutically acceptable excipients. 34. The pharmaceutical composition of embodiment 33, wherein the one or more additional pharmaceutically active ingredients comprise nilmatrervir or a pharmaceutically acceptable salt thereof. 35. The pharmaceutical composition of embodiment 33, wherein the one or more additional pharmaceutically active ingredients comprise lopinavir or a pharmaceutically acceptable salt thereof. 36. A method of treating one or more of HIV or COVID-19, comprising administering to a patient in need thereof a pharmaceutically acceptable amount of ritonavir form III of embodiment 31, or a pharmaceutical composition of any of embodiments 33 to 35. 37. A method for inhibiting cytochrome P450-3A4, comprising administering to a patient in need thereof a pharmaceutically acceptable amount of ritonavir form III of embodiment 31, or a pharmaceutical composition of any of embodiments 33 to 35. [Example]

[0116] (5.1) Example 1: Method for Obtaining Ritonavir Polymorph "Form III" (5.1.1) Crystallization (micro) Form III was initially confirmed by Raman microscopy analysis of several samples generated during various hot-stage optical microscopy (HSOM) experiments. In each experiment, a small amount (~0.5 mg) of Form II ritonavir was carefully placed on a clean microscope slide. The samples were not covered with a coverslip. A Linkam LTS420 hot stage with a T95 temperature controller was programmed with various temperature ramp procedures, as described in Table 6 below.

[0117] [Table 6]

[0118] Immediately after completion of the hot stage temperature ramp procedure, a few crystals from the sample were transferred to a gold-coated or fused silica microscope slide and analyzed by Raman microscopy.

[0119] (5.1.2) Crystallization (macro) Example 1f A 150.0 mg sample of ritonavir form II, USP lot M-RIT / 0804007, was flattened on a glass slide and measured approximately 1 mm x 17 mm x 17 mm (289 mm 3A solid compact of uniform thickness (approximately 1000 nm) was obtained. The compact was melted in a drying oven by exposing it to temperatures between 125 and 128°C for 17 minutes. The temperature near the sample was measured with a mercury thermometer. Complete melting was confirmed visually. The sample was held at 128°C for an additional 10 minutes to confirm that no Form II crystalline particles remained in the melt. The melt was immediately transferred to a second drying oven, placed near a mercury thermometer measuring 80°C in the same oven, and held there for 37 hours. The undisturbed sample on a glass slide was removed from the oven and observed under crossed polarizers with an Olympus SZX9 stereo microscope as a dense mat of birefringent needles. The material was removed from the slide, powdered, and analyzed by powder X-ray diffraction, Raman microspectroscopy, and differential scanning calorimetry. This material is designated Sample No. 48-69-07.

[0120] Example 1g A 150.0 mg sample of ritonavir form II, USP lot M-RIT / 0804007, was flattened on a glass slide and measured approximately 1 mm x 17 mm x 17 mm (289 mm 3 A solid compact of uniform thickness (approximately 1 / 4" x 1 / 4") was obtained. The compact was melted in a drying oven by exposing it to temperatures between 125 and 128°C for 27 minutes. The temperature near the sample was measured with a mercury thermometer. The melt was immediately transferred to a second drying oven, placed near a mercury thermometer measuring 80°C in the same oven, and held there for 23 hours. The undisturbed sample on a glass slide was removed from the oven and observed under crossed polarizers with an Olympus SZX9 stereo microscope as a dense mat of birefringent needles. The material was removed from the slide, powdered, and analyzed by powder X-ray diffraction, Raman microspectroscopy, and differential scanning calorimetry. The sample number for this material is 48-89-01.

[0121] Example 1h A 651.4 mg sample of ritonavir form II from USP lot M-RIT / 0804007 was flattened on a glass slide and measured approximately 1 mm x 17 mm x 17 mm (289 mm 3A solid compact with a uniform thickness was obtained, measuring approximately 130°C. The compact was melted in a drying oven for approximately 25 minutes at approximately 130°C. The temperature near the sample was measured with a mercury thermometer. Complete melting was confirmed visually. The melt was immediately transferred to a second drying oven, placed near a mercury thermometer measuring 80°C in the same oven, and held there for approximately 24 hours. The undisturbed sample on a glass slide was removed from the oven, allowed to cool to room temperature, and examined under a microscope, revealing the presence of several crystals. The sample was returned to the second drying oven at 80°C and held overnight. No changes were observed under the microscope. The sample was then transferred to a third drying oven, placed near a mercury thermometer measuring 130°C in the same oven, and melted over approximately 1 minute. The temperature in the oven was slowly reduced to approximately 83°C, and the sample was left overnight. A white / brown solid mass was observed. The sample was removed from the oven and allowed to cool to room temperature. Under a microscope, the material appeared crystalline. A sample was removed from the slide, powdered, and analyzed by X-ray powder diffraction, Raman microspectroscopy, and differential scanning calorimetry. The material was assigned the sample number 01-89-01.

[0122] (5.2) Example 2: Characterization of Form III (5.2.1) Powder X-ray diffraction XRPD patterns of materials crystallized by macrocrystallization were collected using a PANalytical Empyrean diffractometer in Bragg-Brentano geometry with a 45 kV / 40 mA copper source (Cu K-α1). Silicon standard samples were analyzed to confirm instrument alignment. Prior to analysis, samples were loaded into a silicon zero-background diffraction holder with a 10 x 0.2 mm well and analyzed in reflection geometry. The X-ray source consisted of a 0.04 rad Soller slit, a 1 / 4° fixed antiscatter slit, a 4 mm mask, and a 1 / 16° fixed divergence slit. The diffracted beam reached the detector through a 7.5 mm antiscatter slit and a 0.02 rad large Soller slit. Diffraction patterns were collected using Data Collector software v.6.1b using a PIXcel3D-Medipix3 1x1 detector placed 240 mm from the sample. Data were acquired using 12 repeats of consecutive scans from 2 to 40° 2θ while rotating the sample with a rotation time of 2 seconds.

[0123] (5.2.2) Indexing and Pauly refinement Topas6 (TOPAS6.0.0.9, 2018, Bruker AXS GmbH, Karlshruhe, Germany) was used for indexing and Pauli refinement. 2 All parameters were refined simultaneously until convergence to 0.001. The refined unit cell parameters, space group, and fitting residuals were determined, along with a graphical representation of the Pauly refinement results. Further refinement parameters included, but were not limited to, the following: the background was modeled using Chebyshev polynomial functions and a 1 / x contribution to account for air scattering. If necessary, even broader scattering features could be modeled with contributions from broad ab initio peaks.

[0124] The Bragg peak is broadened by Gaussian crystallite size (τ G ) and Lorentzian strain broadening (ε LThe peak asymmetry due to axial divergence was modeled using the Simple Axial Model (SAM) with a starting value of 10 mm. The sample displacement (d samp ) / zero error (z0) correction was used to account for Bragg peak shifts and, if used, is noted in the parameter table.

[0125] (5.2.3) Differential scanning calorimetry DSC was performed using a TA Instruments Model Q10 Differential Scanning Calorimeter. The instrument was calibrated with indium. Samples were placed in standard aluminum DSC pans, lids were attached, and the weights were accurately recorded. The aluminum pan configured as the sample pan was placed on the reference side of the cell. The pan lid was crimped on before sample analysis. Samples were analyzed in a single run from 25°C to 200°C under a nitrogen gas atmosphere at a heating rate of 10°C / min.

[0126] (5.2.4) Hot Stage Optical Microscope (HSOM) Analysis was completed using an Olympus BX51TRF polarizing microscope with crossed polarizers, a LM PLAN FL N objective with 20x magnification, a 0.40 numerical aperture, and a primary red compensator (530 nm). Heating was performed using a Linkam LTS420 hot stage and a T95 LinkPad system controller. Images were acquired using a Lumenera Series Infinity 3-3URC (Teledyne Lumenera, Ottawa, Ontario, Canada) digital camera. Image capture and processing were performed using Image-Pro® version 10.0.12 build 7452 (date: April 1, 2020).

[0127] The melting point determination method was investigated using sample 48-69-07 from the macrocrystallization experiment. A small piece of the sample was placed on a rigorously clean microscope slide. The sample was covered with a No. 1 1 / 2 cover glass. The Linkam hot stage system controller was programmed with the following temperature ramp routine: 1) Heat at 5.00°C / min to 113.7°C. 2) Heat at 2.00°C / min to 119.0°C. Thermal stability was assessed by sequentially exposing Form III to 50°C, 70°C, and then 90°C for 15 minutes at each temperature, followed by Raman analysis (Sample 50-54-01).

[0128] (5.2.5) Thermogravimetric analysis TG analysis was performed on a TA Instruments Discovery TGA 55 using platinum sample and reference pans. Temperature calibration was performed using nickel. The sample was placed in the pan and heated from ambient temperature to a final temperature of 200 °C in 10 min under a 40 mL / min balance nitrogen purge.

[0129] (5.2.6) Dynamic water vapor sorption DVS isotherms were measured using a VTI SGA-100 Vapor Sorption Analyzer. Samples were not dried prior to analysis. Adsorption and desorption isotherms were collected under a dry air purge at 5% to 95% RH in 10% RH increments. The equilibrium criteria used for analysis were a weight change of less than 0.0100% in 5 minutes, a maximum equilibration time of 3 hours, and a data logging interval of 2 minutes. Data were not corrected for the initial moisture content of the sample.

[0130] (5.2.7) Raman Microscopy Analysis Raman spectra were collected using a HORIBA Scientific XploRA series confocal Raman microscope (Piscataway, NJ) with the following parameters: 785 nm laser (at 100% power), 1200 g / mm grating, 300 micrometer confocal hole, 100 micrometer slit entrance to the spectrometer, 1 second spectral acquisition, and 30 accumulations. The Raman signal was detected using a Syncrity Model 356399 thermoelectrically cooled CCD detector. Spectra were recorded at 125 cm. -1 ~1800cm -1The images were acquired at a range of 520.7 cm. An Olympus Series BX51TRF polarized light microscope (Olympus America Inc., Melville, NY) provided the base optical platform. An Olympus MPlan N Series 20X, 0.40 NA microscope objective was used to focus the laser light onto the sample and collect the Raman signal. The microscope was equipped with a Marzhauser Wetzlar computer-controlled mapping stage to translate the sample for focusing and data acquisition. Digital images were acquired with a Lumenera Series Infinity 3-1C (Teledyne Lumenera, Ottawa, Ontario, Canada) camera using Infinity software version 6.5.6 and Infinity Analyze software version 7.0.2.930 (build date May 1, 2020). Prior to each analysis, a 520.7 cm -1 System calibration was performed using a silicon disk monitoring the peak position of the . All calibrations passed specification before data collection.

[0131] Samples were prepared by dispersing small amounts of material from the hot-stage melt-recrystallization experiments into thin layers on either gold-coated or fused silica microscope slides using a tungsten needle. Small samples were illuminated with white light at 200x magnification to allow for analysis of specific sample areas. Whenever possible, analysis was performed on microscopically apparent single crystals.

[0132] The same instrument parameters were used for all Raman microspectroscopy data collection. Other instrument parameters Autofocus: On Auto exposure: Off Spike Filter: Multiple Accumulation Delay time: 0 seconds Binning: 1 Readout mode: Signal Noise Reduction: Mild ICS correction: Off Dark compensation: Off Instrument Processing: Off Detector gain: highest dynamic range Detector ADC: 45kHz Laser polarization: circular polarization Raman polarization: None Collection time: 1 minute 30 seconds

[0133] (5.3) Example 3: Stability (5.3.1) Temperature and humidity stress Samples of Form III ritonavir were stored at 40° C. and 75% RH. XRPD was measured at days 30, 60, and 96 (FIG. 15). The presence of Form I was detected beginning at day 60. No changes were observed when using amorphous or Form I ritonavir material (Table 5).

[0134] (5.3.2) Manual Polishing A sample of Form III ritonavir was manually ground using a mortar and pestle for five cycles of 2 minutes each (total 10 minutes). XRPD analysis of the finished product showed it to be amorphous with traces of Form III (Figure 16). The amorphous form remained unchanged after grinding. When Form I was used, a mixture of amorphous and Form I was obtained, and when Form II was used, a mixture of amorphous and Form II was obtained.

[0135] (5.3.3) Compression A sample of Form III ritonavir was compressed at 700 lbs. XRPD analysis showed no change before or after compression. Similar results were obtained using amorphous or Form I.

[0136] (5.4) Example 4: Solubility (5.4.1) Sample preparation and analysis Approximately 24 mg of Form I, approximately 60 mg of Form I, Form II, and amorphous material were weighed into 11 separate 20 mL scintillation vials each containing 2 mL of 0.1 N hydrochloric acid and a magnetic stir bar. Each vial was capped and placed in a heated / cooled dry block (Torrey Pines) on an orbital shaker (Four E's) adjusted to 210 rpm. The vials were shaken at ambient conditions for up to 48 hours. At the following time points (0, 10, 20, 30, 45, 60, 75, 120, 360, 720, 1440, and 2880 minutes), the contents of one vial / form were centrifuged at 5000 rpm for 5 minutes to obtain a clear supernatant. If necessary, the supernatant was transferred to a clean tube and recentrifuged for an additional 5 minutes. Each supernatant was diluted 10-fold with 0.1 N hydrochloric acid and analyzed by UV / visible spectroscopy after 0, 10, 20, 30, 45, 75 min, 2 h, 6 h, 12 h, 24 h, and 48 h.

[0137] (5.4.2) Preparation of Standards Approximately 30 mg of Form II ritonavir was accurately weighed into a 5 mL volumetric flask, 3 mL of methanol was added to dissolve the solids, and then diluted with methanol to produce a 6 mg / mL stock solution. Standard solutions ranging from 0.5 mg / mL to 5 mg / mL were prepared by diluting the stock solution with methanol and further diluting each solution with 0.1 N hydrochloric acid, to obtain a calibration curve ranging from 0.05 mg / mL to 0.6 mg / mL.

[0138] (5.4.3) UV / visible spectroscopy All analyses were performed using a Photonics CCD Array UV / Visible spectrophotometer equipped with a deuterium lamp, a fiber optic dip probe (0.2 cm path length) using the 200-450 nm range, and Spectral Instruments SI 400 Series Spectrophotometer Software Part #1657, Rev. C software. Between all measurements, the dip probe was washed with water and methanol. Prior to measurements, the spectrophotometer was blanked with 0.1 N hydrochloric acid.

[0139] (5.4.4) Collection of solid samples After 12-, 24-, and 48-hour solubility tests of Form I, Form II, Form III, and amorphous material, the solids remaining after centrifugation were resuspended in the remaining supernatant, filtered using a nylon filter (Swinnex system, Omnipore 0.2 μm, nylon filter, lot number 0000160371), and air-dried.

[0140] (5.4.5) Powder X-ray diffraction analysis XRPD patterns were collected as described above, except that data were acquired from 2 to 40° 2θ for up to six cycles while rotating the sample with a rotation time of 2 seconds.

[0141] 6. Equivalents and Incorporation by Reference While the claimed invention has been particularly illustrated and described with reference to a preferred embodiment and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and detail can be made therein without departing from the spirit and scope of the disclosure.

[0142] All references, issued patents, and patent applications cited within the body of this disclosure, including but not limited to priority claims to U.S. Provisional Application No. 63 / 510,042, filed June 23, 2023, U.S. Provisional Application No. 63 / 404,090, filed September 6, 2022, and U.S. Provisional Application No. 63 / 403,258, filed September 1, 2022, which are hereby incorporated by reference, are hereby incorporated by reference for all purposes.

Claims

1. The process of melting the ritonavir sample, A step of cooling the sample to a first temperature within the nucleation temperature range during the nucleation period, wherein the nucleation temperature range is approximately 75°C to approximately 100°C. A step in which the crystallization of morphological form III ritonavir is substantially completed during the nucleation period, wherein the nucleation period is between 1 hour and 23 hours. The process of obtaining ritonavir in form III, A method for obtaining ritonavir of form III, including the form III.

2. During the nucleation period, the temperature is maintained at a first temperature, A step of raising the sample from the first temperature to the second temperature, The method according to claim 1, further comprising, wherein the first and second temperatures are within the nucleation temperature range.

3. The method according to claim 1, wherein the X-ray powder diffraction pattern of morphology III ritonavir includes peaks at approximately 7.9° and 9.1°.

4. The method according to claim 1, wherein the form of the ritonavir sample to be melted is selected from amorphous ritonavir, ritonavir form I, and ritonavir form II.

5. The method according to claim 4, wherein the morphology of the ritonavir sample to be melted is ritonavir of morphology II.

6. The method according to claim 1, wherein the melting step includes raising the temperature of the sample to a melting temperature of 125°C or higher.

7. The method according to claim 6, wherein the melting temperature is approximately 125°C to approximately 128°C.

8. The method according to claim 6, wherein the form of the ritonavir sample to be melted is ritonavir form II, the melting temperature is higher than the melting point of ritonavir form II, and the melting is maintained until no seed crystals of form II are present in the melt.

9. The method according to claim 6, wherein the melting temperature is maintained for at least two minutes.

10. The method according to claim 6, wherein the melting temperature is maintained for at least 15 minutes.

11. The method according to claim 6, wherein the melting temperature is maintained for a period of about 15 minutes to about 30 minutes.

12. The method according to claim 1, wherein the nucleation temperature range is approximately 70°C to approximately 85°C.

13. The method according to claim 12, wherein the first nucleation temperature is approximately 80°C.

14. The method according to claim 1, wherein the resulting ritonavir of form III comprises a mixture of amorphous ritonavir and ritonavir of form III.

15. The method according to claim 1, wherein the crystallization of the sample is substantially completed during the nucleation period.

16. The method according to claim 1, further comprising the step of cooling the obtained ritonavir of form III, wherein the obtained ritonavir of form III is cooled to a temperature below the glass transition temperature of amorphous ritonavir.

17. The obtained ritonavir of form III is formed within the nucleation temperature range, according to the method of claim 1.

18. The method according to claim 1, wherein the amount of ritonavir in the sample to be thawed is between approximately 0.5 mg and approximately 5000 mg.

19. The method according to claim 1, wherein the melting process is completed when no crystalline material is present when observed by a hot-stage optical microscope (HSOM).

20. The method according to claim 1, wherein the nucleation period is carried out under reduced gravity conditions.

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