Method and system using a low volatility solvent for spray drying

Abstract

A pharmaceutical formulation, a method for spray drying a pharmaceutical formulation, and a system for spray drying a pharmaceutical formulation are provided. In one example, a method for spray drying a pharmaceutical formulation includes selecting a solvent mixture comprising a low volatility solvent based on the solubility of the drug of the pharmaceutical formulation in the solvent mixture, forming a solution of the drug of the pharmaceutical formulation in the solvent mixture, and spray drying the solution using a spray drying mass ratio, wherein the spray drying mass ratio is selected based on the relationship between the glass transition temperature of the pharmaceutical formulation and the relative saturation of the low volatility solvent during spray drying, the spray drying mass ratio defines the supply rate of the solution relative to the gas supply rate of the drying gas, and using a process outlet temperature lower than the glass transition temperature of the pharmaceutical formulation, and may include spray drying.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Application No. 63 / 367,898, titled "METHODS AND SYSTEMS FOR USE OF LOW - VOLATILITY SOLVENTS FOR SPRAY DRYING", filed on July 7, 2022. The entire content of the above - identified application is incorporated herein by reference for all purposes.

[0002] This description generally relates to the preparation of pharmaceutical formulations using low - volatility processing solvents for spray drying.

Background Art

[0003] Spray drying is a technique commonly used in the manufacture of pharmaceuticals. For example, spray drying can be used as an efficient method for removing solvents, to produce powders with a defined particle size distribution for downstream processing, and / or to produce amorphous solid dispersions to enhance the biopharmaceutical performance of pharmaceutical compounds (e.g., drugs). In many cases, specific materials or excipients are combined with the pharmaceutical compound in a solvent. However, many pharmaceutical compounds have low solubility in the organic solvents commonly used for spray drying.

Summary of the Invention

Problems to be Solved by the Invention

[0004] The boiling point of a common spray-drying solvent, or a mixture thereof, is usually 100 °C or lower (for example, acetone, methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran, methylene chloride, water, etc.). A low-boiling solvent or solvent system is advantageous for spray drying. This is because when the boiling point is high, the process temperature during spray drying usually becomes high, which may lead to a decrease in the chemical and / or physical stability of the compound, the complexity of the equipment, or other process problems. However, despite the advantage of a low boiling point, some pharmaceutical compounds have low solubility in these low-boiling solvents, so the production throughput of formulations (for example, amorphous dispersions) containing these compounds decreases dramatically.

[0005] In many cases, the solubility of these compounds is significantly higher in solvents such as dimethyl sulfoxide (DMSO), n-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF), n,n-dimethylacetamide (DMAC). However, as these solvents have a high boiling point (for example, exceeding 150 °C), they are less volatile, and their use in spray drying is usually avoided. In spray drying using these solvents, the processing temperature usually becomes high, and there is a possibility that pharmaceutical compounds and excipients may deteriorate. Also, a high level of residual solvent may remain in the spray-dried material, and it may be difficult to remove it to an acceptable level for in vivo use.

Means for Solving the Problems

[0006] In one example, the above problem can be at least partially addressed by a pharmaceutical formulation, a method for preparing a pharmaceutical formulation, and a system for preparing a pharmaceutical formulation. The method for preparing a pharmaceutical formulation includes selecting a solvent mixture comprising a first proportion of a low volatility solvent and a second proportion of a high volatility solvent based on the solubility of the drug of the pharmaceutical formulation in the solvent mixture, forming a solution of the drug of the pharmaceutical formulation in the solvent mixture, and spray drying the solution using a spray drying mass ratio to form a dispersion, wherein the spray drying mass ratio is selected based on the relationship between the glass transition temperature of the pharmaceutical formulation and the relative saturation of the low volatility solvent during spray drying, the spray drying mass ratio defines the liquid feed rate of the solution relative to the gas feed rate of the drying gas during spray drying, and using an outlet temperature lower than the glass transition temperature of the pharmaceutical formulation. In this way, the solubility of the pharmaceutical compound can be increased during the spray drying process, while at the same time improving the processing throughput and reducing temperature-related problems.

[0007] It should be understood that the above summary is provided to introduce, in a simplified form, a selection of concepts that are further described in the detailed description. This is not intended to identify key or essential features of the claimed subject matter, the scope of which is uniquely defined by the claims that follow the detailed description. Further, the claimed subject matter is not limited to implementations that solve any disadvantages described above or in any part of this disclosure.

Brief Description of the Drawings

[0008]

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DETAILED DESCRIPTION OF THE INVENTION

[0009] The following description relates to a system and method for treating pharmaceutical compounds, also referred to herein as drugs, using a low volatility solvent. The low volatility solvent can be combined with one or more high volatility solvents to make the pharmaceutical compound into an excipient(s) and solution prior to spray drying, for example, according to the workflow shown in FIG. 1. The resulting spray dried dispersion of the pharmaceutical compound and excipient(s) may be referred to herein as a pharmaceutical formulation. As used herein, the term "low volatility solvent" refers to a solvent having a boiling point of at least 110°C, while the term "high volatility solvent" refers to a solvent having a boiling point of less than 110°C (e.g., 100°C or less). For example, the low volatility solvent(s) can be mixed with the high volatility solvent(s) in a ratio selected to optimize throughput, yield, and temperature, such as according to the methods of FIGS. 7 and 8. The processing parameters can be defined by a process map such as that shown in FIG. 2. This is done by defining a process outlet temperature equal to the glass transition temperature of the material being spray dried at each spray drying mass ratio. As used herein, the spray drying mass ratio refers to the ratio of the mass of the liquid to the mass of the drying gas supplied to the spray dryer. The spray drying mass ratio may also be referred to as the L / G ratio, as further described below. For example, as shown in FIGS. 3 and 4, if the process outlet temperature is higher than the glass transition temperature at a given spray drying mass ratio, the yield may decrease. For example, the relationship between the relative saturation of the low volatility solvent and the glass transition temperature can be determined by examining the uptake of the solvent by the material at different relative saturations of the solvent and measuring the corresponding glass transition temperature, such as shown in FIGS. 5 and 6. FIG. 9 identifies various combinations of process conditions based on desirability to improve both throughput and yield. In this way, by including a low volatility solvent, the solubility of the pharmaceutical compound in the spray drying solvent can be increased while avoiding high outlet process temperatures that can cause degradation, and as a result, the throughput and yield of compounds that are relatively low in solubility in the high volatility solvents normally used during spray drying may increase.

[0010] Figure 1 shows a workflow 100 for processing a pharmaceutical compound (e.g., a drug) by spray drying a solution having a mixture of at least one low volatility solvent and at least one high volatility solvent. Workflow 100 includes a process tank 102 that is initially empty. A low volatility solvent 104 and a high volatility solvent 106 are each added to the process tank 102 to form a solvent blend 108. The low volatility solvent 104 can be selected, for example, from dimethyl sulfoxide (DMSO), n-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF), and n,n-dimethylacetamide (DMAC). In particular, DMSO can be selected as the low volatility solvent 104 because, as further described below, there may be residual low volatility solvent remaining after spray drying and the allowable exposure limit is relatively high. The high volatility solvent 106 can be selected, for example, from acetone, alcohols (e.g., methanol, ethanol, isopropanol, n-propanol), acetonitrile (ACN), tetrahydrofuran (THF), methylene chloride (DCM), ethyl acetate (EtOAc), n-methyltetrahydrofuran, chloroform, hexanes (e.g., n-hexane), acetic acid, cyclohexane, ethers (e.g., ethyl ether), and water. As will be described in detail with respect to Figure 8, the specific solvents used, as well as the ratio of the low volatility solvent 104 to the high volatility solvent 106 within the solvent blend 108, can be optimized to increase process throughput, increase yield, and decrease process temperature. For example, a pharmaceutical compound may be more soluble in the low volatility solvent 104 than in the high volatility solvent 106, and the low volatility solvent 104 may be more difficult to remove by spray drying than the high volatility solvent 106. Further, in some examples, the low volatility solvent 104 and / or the high volatility solvent 106 may include more than one solvent. For example, the high volatility solvent 106 may be a blend of two or more high volatility solvents, such as a blend of methanol, acetone, and DCM at a selected ratio (e.g., weight percent or volume percent). As used herein, a blend of solvents may refer to a miscible mixture of solvents that cannot be physically separated.

[0011] High-volatility solvents and low-volatility solvents are defined in terms of their boiling points at atmospheric pressure. However, it has been recognized that the vapor pressure of the solvent at the temperature used in spray drying is a more relevant parameter in determining the yield and quality of the spray-dried dispersion. Generally, the higher the vapor pressure, the lower the boiling point, and vice versa. However, the magnitude of the effect of switching between two solvents with different boiling points can only be recognized by comparing their vapor pressures. Referring to FIG. 10 as an example, a graph 1000 of the vapor pressure of DMSO versus temperature is shown. Plot 1002 corresponds to the relative vapor pressure of DMSO and is 1 at all temperatures when the y-axis is given for DMSO. Plot 1004 corresponds to the vapor pressure of DMF relative to DMSO, and plot 1006 corresponds to the vapor pressure of DMAC relative to DMSO. The boiling point of DMSO is 189°C (462K), which is higher than the boiling points of DMF (153°C / 426K) and DMAC (165°C / 438K), but does not exceed 10% on the absolute temperature scale. On the other hand, as shown in graph 1000, the vapor pressures of DMF and DMAC can be 2 to 7 times greater depending on the temperature. The effects of selecting DMSO compared to DMF or DMAC as the low-volatility solvent will be further described below.

[0012] Returning now to FIG. 1, a drug 110 and one or more excipients 112 are added to a solvent blend 108 within a process tank 102 to form a solution 114. For example, the drug 110 may be a crystalline form of a pharmaceutical compound having relatively low bioavailability, stability, and / or water solubility, and the one or more excipients 112 may be polymers that, when blended with the drug 110, increase its bioavailability, stability, and / or water solubility. For example, the one or more excipients 112 may include derivatives of cellulose (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose acetate succinate, etc.) or sugars such as sugars (e.g., xylitol, lactose, etc.), proteins (e.g., gelatin), and / or synthetic polymers (e.g., methacrylic acid·methyl methacrylate copolymer or polyvinylpyrrolidone).

[0013] Workflow 100 shows that drug 110 and one or more excipients 112 are added to solvent blend 108, but other addition sequences are possible. For example, drug 110 can be added to low volatility solvent 104 to form a first solution containing drug 110 and low volatility solvent 104. Then, high volatility solvent 106 can be added to the first solution to form a second solution containing drug 110, low volatility solvent 104, and high volatility solvent 106. Further, one or more excipients 112 can be added to the first solution or the second solution. As another example, one or more excipients 112 can be added to low volatility solvent 104, high volatility solvent 106, or solvent blend 108 either simultaneously with or at different times relative to drug 110 (e.g., before drug 110, after drug 110, or simultaneously with drug 110). Further, if multiple excipients are included in one or more excipients 112, the individual components of one or more excipients 112 can be added to the solvent(s) either all at once or individually. Thus, solution 114 can be formed by various addition sequences. Further, agitation can be used to facilitate mixing within process tank 102.

[0014] Optionally, heat 116 can be applied to solution 114 to aid dissolution. For example, the solubility of drug 110 in solvent blend 108 can be higher at temperatures above ambient temperature. However, solution 114 can be maintained below a temperature at which drug 110 or one or more excipients 112 may begin to decompose.

[0015] Solution 114 is supplied to a spray dryer 118 configured to receive solution 114 from process tank 102 at a liquid feed rate (L). Generally, as the concentration (e.g., percentage) of the low volatility solvent 104 in solvent blend 108 increases, the liquid feed rate may decrease. Solution 114 may flow through the spray nozzles of spray dryer 118, which divides the liquid stream into a spray of droplets of a controlled size. Spray dryer 118 may be configured to receive drying gas 120 at a gas feed rate (G). The ratio of the liquid feed rate to the gas feed rate is referred to herein as the L / G ratio. For example, the liquid feed rate may refer to the mass of solution 114 processed per unit time, and the gas feed rate may refer to the mass of drying gas 120 flowing through spray dryer 118 per unit time. Thus, the L / G ratio may represent the ratio of the mass of solution 114 to the mass of drying gas 120 entering spray dryer 118. In this specification, the L / G ratio may also be referred to as the spray drying mass ratio.

[0016] Drying gas 120 (which may be, for example, air or nitrogen) may be heated to the drying gas inlet temperature via heating element 122 of spray dryer 118, and the heated drying gas 120 contacts the spray to evaporate solvent blend 108, forming an amorphous dispersion of drug 110 and one or more excipients 112, resulting in an output composed of spray dried formulation 124. The temperature achieved at the outlet of spray dryer 118 may be increased or decreased by adjusting heating element 122, and thus by adjusting the drying gas inlet temperature. The temperature achieved at the outlet of spray dryer 118 may be referred to herein as the process outlet temperature. As will be described in more detail below, the process outlet temperature may be selected according to the L / G ratio. For example, a typical outlet temperature of spray dryer 118 may range from 35 to 55 °C when pure acetone is used, but may range from 50 to 120 °C when a mixture of DMSO and acetone is used. The selection of the process outlet temperature will be further described below with reference to Figure 2. In some examples, the spray dried formulation 124 may be subjected to secondary drying. However, during spray drying in dryer 118 and during secondary drying, the temperature may be kept below the boiling point of the low volatility solvent 104.

[0017] Solvent removal during the spray drying process is affected by both kinetic and thermodynamic properties, such as the equilibrium partitioning of the solvent between the vapor phase and the spray-dried formulation 124. The kinetic and thermodynamic properties depend on the identity of the low volatility solvent(s) 104 and high volatility solvent(s) 106 in the solvent blend 108, as well as their ratio, and can give rise to processing constraints on the spray drying process. The amount of low volatility solvent(s) 104 in the solvent blend 108 may range from 0 to 100%. For example, the solvent blend 108 may include a first proportion of low volatility solvent(s) 104 and a second remaining proportion of high volatility solvent(s) 106. As an example, the low volatility solvent(s) 104 may comprise at least 10% (e.g., by weight or volume) of the solvent blend 108. However, as the proportion of low volatility solvent(s) 104 in the solvent blend 108 increases, the process outlet temperature of the spray drying process may increase and / or the process rate of the spray drying (e.g., liquid feed rate) may decrease in order to assist in solvent removal.

[0018] For the spray drying process to be successful, a process outlet temperature (T g ) lower than the glass transition temperature (T out ) of the spray-dried product (e.g., the spray-dried formulation 124 of FIG. 1) is used. The spray-dried product contains an active pharmaceutical ingredient (e.g., a drug), excipient(s), and residual solvent. If the process outlet temperature is higher than the T g of the spray-dried product, the material adheres to the surface of the apparatus and an unacceptably low yield occurs. Furthermore, the physical stability of the spray-dried product may decrease dramatically if it is maintained above the glass transition temperature. The glass transition temperature of a spray-dried product containing a large amount of residual solvent is referred to as the "wet T g " as opposed to the "dry T g " observed when all of the residual solvent has been removed from the product. The wet T g is lower than the dry T g .

[0019] When designing a spray drying process, if the process outlet temperature is high, the relative saturation of the solvent in the vapor stream decreases compared to when the process outlet temperature is low with the same raw material supplied at the L / G ratio, resulting in a drier product. Therefore, as the residual solvent in the product decreases, it is expected that the wet T g will increase when the process outlet temperature rises. Since it is difficult to predict in advance the thermodynamic principles involved in determining the magnitude of this effect, it cannot be easily predicted whether an increase in ΔT of the process outlet temperature will cause the wet T g to change by more or less than the magnitude of ΔT. Due to these competing effects, there are finite upper and lower threshold values for the process outlet temperature to ensure the chemical and physical stability of the product. According to the embodiments described herein, these upper and lower threshold values are functions of the L / G ratio in the spray dryer, and the relationship between these threshold values and the L / G ratio will depend on the formulation composition and the solvent system. As used herein, the term "solvent system" may refer to a mixture of one or more solvents in a defined ratio, or a single solvent. For example, the solvent system may include a solvent mixture (or solvent blend) containing one or more low volatility solvents and / or one or more high volatility solvents, a single low volatility solvent, or a single high volatility solvent. For example, a solvent mixture is a solvent system containing a plurality of solvents (e.g., a mixture of different solvents).

[0020] For example, referring briefly to FIG. 2, an exemplary process map 200 for spray drying a pharmaceutical formulation from a solvent mixture using DMSO is shown. The vertical axis of the process map 200 represents the L / G ratio (e.g., calculated based on the mass fraction of DMSO in the solvent feed), and the horizontal axis represents the process outlet temperature T out . Since more material is processed per unit time, an increase in the L / G ratio corresponds to an increase in the throughput of spray drying. The process map 200 shows the wet T gIt includes an equivalent plot 202 equal to the process outlet temperature when spray-drying H-grade hypromellose acetate succinate (HPMCAS-H), which is an excipient, from 100% DMSO. The equivalent plot 202 can be determined empirically according to the relative saturation of DMSO, as will be further described below with respect to FIG. 5.

[0021] The process map 200 can generally be divided into a plurality of regions including a first region 204 bounded by a dotted line 201, a second region 206 bounded by a combination of the dotted line 201, a dashed line 203, and the equivalent plot 202, a third region 208 bounded by a combination of the dotted line 201 and the dashed line 203, and a fourth region 210 bounded by a combination of the equivalent plot 202, the dotted line 201, and the dashed line 203. The first region 204 corresponds to a high process outlet temperature and a relatively low L / G ratio, the second region 206 corresponds to a lower process outlet temperature and a relatively high L / G ratio, the third region 208 corresponds to a relatively low process outlet temperature and a relatively low L / G ratio, and the fourth region 210 corresponds to a relatively low process temperature and a relatively high L / G ratio. Although there are overlaps between the process outlet temperatures and / or L / G ratios included in the various regions, each region defines a different combination of process outlet temperature and L / G ratio.

[0022] FIG. 2 further includes a key 212 that defines different spray-dried dispersions according to different symbols. The upright white triangle symbol represents a prior art L-grade HPMCAS formulation. The white diamond symbol represents a prior art hydroxypropyl methylcellulose (HPMC) formulation. The upright black triangle symbol represents a prior art polyvinylpyrrolidone (PVP) formulation. The downward black triangle represents a prior art 100% active formulation. The circle represents spray-dried HPMCAS-H from a solvent system containing DMSO according to the present disclosure, and the V symbol represents a spray-dried dispersion of vemurafenib, an active pharmaceutical ingredient having HPMCAS-H from a solvent system containing DMSO according to the present disclosure. It will be understood that the dispersions are mapped according to the mass fraction of DMSO in the solvent feed.

[0023] As described above, in order to avoid a decrease in the yield and physical instability of the spray-dried product, it is desirable to carry out the spray-drying process at a process outlet temperature lower than wet T g Therefore, the equivalent plot 202 may define an upper threshold value of the process outlet temperature as a function of the L / G ratio, and define the desired processing space of the process map 200. Since the fourth region 210 is located entirely above the equivalent plot 202, it is not desirable to perform spray drying using the conditions (for example, the combination of the L / G ratio and T out in the fourth region 210).

[0024] Furthermore, it is not desirable to carry out the spray-drying process using the conditions in the first region 204 because the throughput decreases due to the relatively low L / G ratio. Furthermore, when the material to be spray-dried is temperature-sensitive, physical instability and / or chemical decomposition may occur due to a relatively high temperature (for example, 90 °C or higher). When the material to be spray-dried is not temperature-sensitive, if spray drying is carried out using the conditions in the second region 206 instead of the first region 204, the throughput may increase because the L / G ratio in the second region 206 is high. In particular, conventional formulations are concentrated within the first region 204. However, in some examples, it can be understood that the drying T g of the shown formulation may exceed the T g of pure HPMCAS-H. For example, some polymers contain PVP having a higher T g than HPMCAS, while other polymers contain active pharmaceutical ingredients that may raise the T g of the formulation (for example, as can be seen from the fact that it can be spray-dried at T out = 120 °C).

[0025] As another example, when performing the spray drying process using the conditions in the third region 208, although the throughput may decrease, it may be possible to spray dry temperature-sensitive formulations such as some biopharmaceuticals. However, it may be desirable to spray dry formulations with low temperature sensitivity using the conditions in the second region 206 that include both a lower outlet temperature (e.g., lower than the first region 204) and a higher throughput (e.g., higher than the first region 204).

[0026] In particular, when the outlet temperature is 78 °C and the L / G ratio is 0.0128, the throughput is maximized (e.g., when the equivalent plot 202 is maximized). Since the process conditions may change during operation, by using the equivalent plot 202 to define the process conditions, it is also possible to optimize the process based on robustness considerations. For example, by reducing the L / G ratio by 3% from its maximum value of 0.0128 at 78 °C (e.g., to 0.0124 at 78 °C), a process outlet temperature variation of up to 5 °C can be tolerated. That is, the L / G ratio may be maximized so that the variation of T out due to the variation of wet T g does not exceed T out . Alternatively, considering the robustness against variations in the L / G ratio with T out held at a constant value may also be considered. As an example, based on how accurately the L / G ratio or T out can be controlled in a particular process, the process can be optimized to maintain the L / G ratio at a constant value or to maintain T out at a constant value.

[0027] In some examples, the second region 206 may be defined by a lower spray drying mass ratio (e.g., L / G ratio) threshold and an upper process outlet temperature threshold in addition to the equivalence plot 202. The lower spray drying mass ratio threshold and the upper process outlet temperature threshold may be a single value or may vary. For example, the upper process outlet temperature threshold may be linear or curved with respect to the L / G ratio and / or vice versa (e.g., the lower mass ratio threshold may vary with respect to the process outlet temperature). The second region 206 may include an L / G ratio greater than the lower spray drying mass ratio threshold and a process outlet temperature lower than the upper process outlet temperature threshold. As a non-limiting example, the lower spray drying mass ratio threshold is 0.004 as shown by the dotted line 203, which defines the boundary between the second region 206 and the third region 208 in this example. The process conditions within the second region 206 may be advantageous for spray drying small molecule-based pharmaceutical formulations, while the processing conditions within the third region 208 may be advantageous for spray drying biopharmaceuticals as described above. As another non-limiting example, the upper process outlet temperature threshold may be a value within the range of 80-90 °C (e.g., 85 °C).

[0028] As another example, additionally or alternatively, the second region 206 and the third region 208 may be combined such that the second region 206 includes all of the process space outside of the first region 204 that is below the equivalence plot 202. In such an example, the lower mass ratio threshold may be determined based on the process outlet temperature relative to a predetermined temperature threshold. The predetermined temperature threshold may distinguish between the process conditions for small molecule-based formulations and the process conditions for biopharmaceuticals. The lower mass ratio threshold may be high when the process outlet temperature is above the predetermined temperature threshold and low when the process outlet temperature is below the predetermined temperature threshold. As an example, the predetermined temperature threshold may be 60 °C. In this example, when the process outlet temperature is 60 °C or higher, the lower spray drying mass ratio threshold may be 0.004, and when the outlet temperature is less than 60 °C, the lower spray drying mass ratio threshold may be 0.001.

[0029] Process map 200 is shown for the HPMCAS-H system, but a similar methodology may be applied to formulations containing an active pharmaceutical ingredient and a polymeric excipient. The T of the active pharmaceutical ingredient g is higher or lower than that of the excipient, g and depending on whether the active pharmaceutical ingredient interacts with the solvent (e.g., as determined by dynamic vapor sorption), the equivalence plot 202 may shift up or down, respectively. As an example, if the active pharmaceutical ingredient causes the formulation to hold more or less solvent at an equivalent relative saturation compared to the excipient alone, the equivalence plot 202 may shift down or up, respectively, compared to the excipient alone. Further, this methodology is extended to mixed solvent systems that combine a highly volatile solvent and DMSO (and / or another low volatility solvent). In particular, the solubility of the active pharmaceutical ingredient (e.g., API) in the mixed solvent system may decrease more slowly with respect to a decrease in the proportion of DMSO than the potential increase in the L / G ratio (e.g., spray drying throughput) that may be enabled by reducing the amount of DMSO in the mixture. This strategy may aim to maximize the process throughput defined as the amount obtained by multiplying the concentration of the active pharmaceutical ingredient and the liquid feed rate (e.g., the amount of API processed per unit time). For example, compared to a 100% DMSO solvent system, the solubility of the active pharmaceutical ingredient decreases by 20% in a 50 / 50 DMSO / acetone, but if the L / G ratio doubles, the API processing rate is improved by using the mixed solvent system.

[0030] Alternatively, the concentration of the active pharmaceutical ingredient may be limited by the maximum allowable excipient concentration of spray drying (e.g., by viscosity limitation and sprayability). In such an example, throughput may be maximized by setting the DMSO composition of the solvent system to the minimum level that allows the maximum allowable excipient concentration. For example, considering the solution viscosity, the desired maximum active pharmaceutical ingredient concentration may be 2% by weight. In this example, if spray drying is possible at 2% by weight of the active pharmaceutical ingredient with a 50 / 50 DMSO / acetone solvent system, there is no advantage in using a higher DMSO ratio even if 100% DMSO can dissolve 20% by weight of the active pharmaceutical ingredient.

[0031] Similar to the approach demonstrated for pure DMSO, wet T g can be determined according to the process outlet temperature of any mixture of the active pharmaceutical ingredient, excipient, and one or more solvents. However, in practice, since highly volatile solvents are usually much more volatile than DMSO, the shape of the equivalent plot 202 is governed by the thermodynamic properties of DMSO. For example, the "optimal" process outlet temperature of 78 °C implied by the equivalent plot 202 in Figure 2 exceeds the boiling points of common spray drying solvents such as acetone, methanol, DCM, and THF. Therefore, the methodology described herein can be used to define the range of process outlet temperatures allowed for spray drying of DMSO-containing solvents according to throughput (e.g., L / G ratio), resulting in a significant increase in throughput and a significant decrease in the process outlet temperature. Hereinafter, an example of how to obtain wet T g will be described with reference to Figures 5 to 6.

[0032] The process map 200 provides information on throughput but does not provide information on the yield of each spray drying process. Such information is provided in Figures 3 and 4. First, referring to Figure 3, for a 10 g batch of HPMCAS-H sprayed from a DMSO solvent blend, the predicted values of T g -T out (e.g., the predicted T g shown on the horizontal axis and T outAn example of a yield plot 300 is shown that indicates the percent yield (vertical axis) according to the difference (from...). The data of the yield plot 300 is separated according to the highly volatile co-solvent used in the solvent blend according to key 302. For example, the data points indicated by white circle symbols relate to HPMCAS-H samples sprayed from a solvent blend containing DMSO and THF, and the data points indicated by white triangle symbols relate to HPMCAS-H samples sprayed from a solvent blend containing DMSO and acetone. The yield plot 300 further includes an isoline 304 where T g is equal to T out which may correspond to the isoplots 202 of Figure 2.

[0033] Specifically, the percent yield is mapped according to the difference between T g and T out . The yield plot 300 shows that when T g - T out is a positive value (for example, when the process outlet temperature used during spray drying is kept below the predicted wet glass transition temperature of the spray-dried material), the yield is relatively insensitive to the magnitude of T g - T out . At these positive T g - T out values, the yield varies around an average value of about 79.7% and the standard deviation is 8.6%, but it can be understood that the yield may vary depending on the specific spray dryer, batch size, and atomization method used. Thus, it can be understood that the yield does not change significantly while spray drying under processing conditions where T out does not exceed T g .

[0034] Furthermore, the yield plot 300 of Figure 3 shows that the yield begins to decrease as the value of T g - T out becomes negative. That is, as expected, when the process outlet temperature of the spray dryer further increases above the predicted wet glass transition temperature of the spray-dried material, the yield decreases. For example, (T g - T out)=-16 °C, the yield of one spray is about 0%, while the yield of another spray is 45%, which is much lower than the average yield when T g -T out is positive. Therefore, the yield plot 300 shows that when T g -T out is positive, the yield is not significantly affected by T g -T out and allows the use of a process outlet temperature lower than the "optimal" temperature (see Figure 2) at which the throughput is maximized without a decrease in yield.

[0035] This conclusion is further supported by the additional exemplary yield plot 400 shown in Figure 4. Similarly, the yield plot 400 shows the percent yield (vertical axis) according to the predicted value of T g -T out for a 5 g batch of HPMCAS-H sprayed from 100% DMSO or a DMSO solvent blend, as indicated by key 402. For example, the data point indicated by the white circle symbol relates to an HPMCAS-H sample sprayed from a solvent blend containing DMSO and THF, the data point indicated by the white triangle symbol relates to an HPMCAS-H sample sprayed from a solvent blend containing DMSO and acetone, and the data point indicated by the white diamond symbol relates to an HPMCAS-H sample sprayed from 100% DMSO. The yield plot 400 further includes an isocurve 404 where T g is equal to T out which may correspond to the isocurve 202 in Figure 2.

[0036] Similar to the yield plot 300 in Figure 3, the yield plot 400 in Figure 4 shows that T g -T outIt shows that the yield decreases as the negative value of [[ID=]] increases. Therefore, although the magnitude of the yield between the yield plot 300 in FIG. 3 and the yield plot 400 in FIG. 4 cannot be directly compared due to the difference in batch size, the yield plot 400 supports the methodology described herein for increasing both yield and throughput by operating at a process outlet temperature below the glass transition temperature determined according to the L / G ratio.

[0037] As shown in FIG. 2, to determine the relationship between the L / G ratio and the equivalent plot, T g is determined according to the relative saturation of DMSO. The relative saturation of DMSO refers to the amount of DMSO in the vapor phase relative to the total amount of DMSO that can be held in the dry gas stream, and 100% refers to a completely saturated dry gas. For example, a relative saturation of DMSO of up to about 50% may be targeted. Referring now to FIG. 5, an exemplary dynamic vapor sorption (DVS) plot 500 is shown, which can be used to define the amount of DMSO uptake in a material according to the DMSO relative saturation. In particular, the DVS plot 500 shows the percentage of weight gain of the sample relative to the initial mass of the sample (vertical axis) similar to the DMSO relative saturation (horizontal axis). The increase in the weight of the sample may be due to the uptake of DMSO by the sample. In this example, the sample contains HPMCAS-H. However, it will be understood that other materials, such as different excipients, active pharmaceutical ingredients, and combinations thereof, can be similarly examined.

[0038] The DVS plot 500 includes a lower curve 502 corresponding to the adsorption of DMSO onto HPMCAS-H and an upper curve 504 corresponding to the desorption of DMSO by HPMCAS-H at a constant temperature (e.g., 50 °C). As the relative saturation of DMSO increases, the amount of DMSO incorporated by HPMCAS-H increases by a measurable amount. Each curve connects four data points corresponding to different DMSO relative saturations, although different numbers of data points and / or samples at different DMSO relative saturations may be used. Samples of HPMCAS-H containing DMSO at multiple DMSO relative saturations are removed from the instrument (e.g., a gravimetric instrument) performing the DVS analysis and further analyzed, for example, by differential scanning calorimetry (e.g., modulated differential scanning calorimetry), to determine their glass transition temperatures (e.g., the wet T g ). For example, samples at each DMSO relative saturation examined may be analyzed.

[0039] Referring now to FIG. 6, the plot 600 shows the T g (vertical axis) of HPMCAS-H as a function of the DMSO relative saturation (horizontal axis). As described above with respect to FIG. 5, HPMCAS-H is used in this example, although other materials may be examined as well to determine the relationship between T g and the DMSO relative saturation. The plot 600 includes a curve 602 connecting the data points for each DMSO relative saturation corresponding to the DMSO relative saturation samples from the DVS plot 500 of FIG. 5.

[0040] Note that the plot 600 in FIG. 6 can be used to establish the relationship between the L / G ratio and the DMSO relative saturation at a given value of T out by combining the mass and energy balance performed in a spray dryer with the known vapor-liquid equilibrium behavior of DMSO, and can be used to determine the relationship between the L / G ratio and the difference between T g and T out . Thus, at a given L / G ratio and T out , the relative saturation of DMSO, and thus the predicted wet T gcan be calculated. Therefore, an equivalent plot such as the equivalent plot 202 of FIG. 2 fixes the L / G ratio and predicts the wet T g until it matches T out can be determined by changing.

[0041] It will be understood that the calculations outlined above can be performed by numerically interpolating between experimental data points and / or by fitting the data to a model in order to use analytical optimization techniques. The practical advantage of an analytical approach is that it is less susceptible to the effects of experimental noise.

[0042] Next, FIG. 7 shows an exemplary method 700 for identifying processing conditions for preparing a pharmaceutical formulation comprising an active pharmaceutical ingredient (e.g., a drug) and excipient(s) by spray drying using at least one low volatility solvent. The spray drying process is used to remove the solvent, and since low volatility solvents are inherently less likely to evaporate than high volatility solvents, method 700 takes into account the thermodynamic considerations of increasing the solubility and stability of the drug while reducing the residual solvent in the spray dried formulation, and the kinematic considerations that make the preparation economically feasible by increasing throughput and yield, there is a possibility of optimizing the use of low volatility solvents for each pharmaceutical formulation.

[0043] At 702, method 700 includes determining a first relationship between the relative saturation of the low volatility solvent (e.g., DMSO) and the glass transition temperature of the material being spray dried. In some examples, the first relationship can be determined for a combination of active pharmaceutical ingredient and excipient(s) according to their ratio in the pharmaceutical formulation or another ratio that enables empirical determination of the first relationship. In other examples, the first relationship can be determined for the excipient(s) alone or the active pharmaceutical ingredient alone, such as whether the glass transition temperature of the active pharmaceutical ingredient is higher or lower than the glass transition temperature of the excipient.

[0044] Furthermore, in some examples, the relationship between relative saturation and glass transition temperature can be determined for a mixed solvent system. For example, the mixed solvent system can include two or more low-volatility solvents (plural possible) mixed in a defined ratio, or a low-volatility solvent mixed with one or more high-volatility solvents (plural possible) in a defined ratio. Thus, although method 700 is described for a low-volatility solvent, it will be understood that method 700 is also applicable to a mixed solvent system.

[0045] Determining the first relationship can include defining the amount of low-volatility solvent(s) taken up by the material according to the relative saturation of the low-volatility solvent(s) via, for example, dynamic vapor sorption. An example of a dynamic vapor sorption plot was described above with respect to FIG. 5. Determining the first relationship can further include analyzing the material at different relative saturations of the low-volatility solvent(s) by modulated differential scanning calorimetry to determine the corresponding glass transition temperature, as described above with respect to FIG. 6.

[0046] Examples of various excipients that can be used include HPMCAS, HPMC, PVP, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), and any combination of various polymethacrylates (e.g., Eudragit® L100 or L100-55) with DMSO, NMP, DMF, and DMAC. In some examples, DMSO can be a desirable low-volatility solvent because it has low toxicity and a relatively high acceptable concentration in the final pharmaceutical product. DMF and / or DMAC are still low-volatility solvents, but have a vapor pressure five times higher than that of DMSO in the general spray drying temperature range of 50°C to 100°C. For this reason, in another example, DMF and / or DMAC may be desirable over DMSO to improve spray drying yield and / or throughput. Furthermore, in some examples, water or methanol may be included up to a threshold ratio (e.g., 5%) to increase the solubility of the polymer in some solvent systems.

[0047] At 704, method 700 includes determining a second relationship between the spray-drying mass ratio (e.g., liquid mass to gas mass, or L / G ratio) and the relative saturation of the low-volatility solvent at a given process outlet temperature based on a first relationship. For example, using the known vapor-liquid equilibrium behavior of the low-volatility solvent, the relationship between the L / G ratio and the relative saturation of the low-volatility solvent at a given process outlet temperature can be established through relationships such as mass and energy balance relationships.

[0048] At 706, method 700 includes calculating the predicted glass transition temperature of the material to be spray-dried at a given spray-drying mass ratio based on the second relationship. For example, since the amount of low-volatility solvent adsorbed on the material affects the glass transition temperature, it may be possible to determine the relative saturation of the low-volatility solvent at a given spray-drying mass ratio.

[0049] At 708, method 700 includes generating a process map that associates the process outlet temperature with the spray-drying mass ratio based on the predicted glass transition temperature at each spray-drying mass ratio. This includes generating an equivalent plot where the predicted glass transition temperature is equal to the process outlet temperature at each spray-drying mass ratio, as shown at 710. The equivalent plot can be generated by interpolating between the data points obtained when determining the first and second relationships, or by analysis optimization techniques such as fitting the data points to a model as described above with respect to FIG. 6.

[0050] At 712, method 700 includes identifying the process outlet temperature corresponding to the maximum throughput (e.g., maximum spray-drying mass ratio) based on the equivalent plot. The process outlet temperature at the maximum throughput can be identified as the overall maximum of the equivalent plot, and the equivalent plot peaks with respect to the L / G ratio.

[0051] At 714, method 700 includes performing spray drying using a process outlet temperature at maximum throughput and optimized parameters (e.g., process parameters) based on solubility and viscosity constraints, as detailed below with respect to FIG. 8. For example, a maximum L / G ratio may be used, and the process outlet temperature used may be below the glass transition temperature at the maximum L / G ratio. As another example, if there are solubility and / or viscosity constraints, a different L / G ratio optimized for the material being spray dried may be used accordingly, and the process outlet temperature may be below the glass transition temperature at the optimized L / G ratio. Thereafter, method 700 ends. For example, method 700 may be repeated for each pharmaceutical formulation to optimize the processing throughput of that formulation.

[0052] Referring now to FIG. 8, an exemplary method 800 is shown for using a low volatility solvent as a processing solvent for preparing a pharmaceutical formulation comprising a drug (e.g., an active pharmaceutical ingredient) and excipient(s) by spray drying. The spray drying process is used to remove the solvent, and since the low volatility solvent is inherently less likely to evaporate than a high volatility solvent, method 800 is based on thermodynamic considerations that increase the solubility and stability of the drug while reducing the residual solvent in the spray dried formulation, and kinematic considerations that make the formulation economically viable by increasing throughput and yield, and can utilize conditions optimized for the spray drying of each pharmaceutical formulation. For example, method 800 may utilize the process conditions determined via method 700 of FIG. 7.

[0053] In 802, method 800 includes selecting one or more low-volatility solvents, one or more high-volatility solvents (if any), and the solvent ratio of the low-volatility solvent(s) to the high-volatility solvent(s) based on the spray-drying mass ratio and process outlet temperature at maximum throughput (see Figure 7), the solubility of the material to be spray-dried, and the viscosity of the material to be spray-dried. As described above, the low-volatility solvent(s) can be selected from, for example, DMSO, NMP, DMF, and DMAC, while the high-volatility solvent(s) can be selected from acetone, methanol, ethanol, isopropanol, ACN, THF, DCM, EtOAc, and water. DMSO can be preferentially selected as the low-volatility solvent because the residual solvent threshold of DMSO is high compared to other low-volatility solvents, whereby the burden of positive secondary drying that can be used together with other solvents having a lower residual solvent threshold can be reduced. Further, DMSO can easily dissolve both polar and non-polar compounds and is miscible with many organic solvents such as water and the high-volatility solvents described herein, thus providing a wide range of applications.

[0054] The amount of the low-volatility solvent(s) in the solvent system can range from 0 to 100%. For example, the solvent system may include a first proportion of the low-volatility solvent(s) and a second remaining proportion of the high-volatility solvent(s). As an example, the low-volatility solvent(s) may include at least 10% (e.g., by weight or volume) of the solvent system. However, as the proportion of the low-volatility solvent(s) in the solvent system increases, the process outlet temperature of spray drying may increase and / or the process speed of spray drying (e.g., liquid supply rate) may decrease in order to assist in the removal of the solvent.

[0055] Therefore, for the process to be viable in terms of yield and throughput, it is desirable to process the solution of the drug and excipient(s) obtained in the solvent system at approximately the maximum L / G ratio and at a process outlet temperature selected according to the L / G ratio. As described above, the L / G ratio refers to the ratio of the liquid mass feed rate (L) to the dry gas mass feed rate (G) supplied to the spray dryer, as described with respect to FIGS. 1-6. Further, the process outlet temperature can be set to reduce chemical and physical decomposition during spray drying and may be lower than the boiling point of the low volatility solvent(s). Thus, the L / G ratio and the process outlet temperature can be selected based on the processing constraints related to the wet T g of the material being spray dried.

[0056] Through empirical testing, using a particular low volatility solvent above a threshold percentage may cause the L / G to decrease and / or the process outlet temperature may need to be increased to remove the low volatility solvent to an acceptable level, relative to the wet T g of the material being spray dried (e.g., if the dispersion is physically stable as a solid and is unlikely to recrystallize during the process related time scale and the residual solvent is below the desired residual solvent threshold level). Further, as described above, the residual solvent threshold level may vary depending on the low volatility solvent, such as being higher in the case of DMSO. Thus, the proportion of a particular low volatility solvent above its residual solvent threshold level may not be considered.

[0057] In order to maximize the throughput of the process, the solubility and viscosity of the material being spray dried are also considered when selecting the low volatility solvent(s), high volatility solvent(s), and their ratio. In particular, reducing the proportion of the low volatility solvent(s) in the solvent system may decrease the solubility of the active pharmaceutical ingredient, but may increase the L / G ratio. As an example, as the proportion of the low volatility solvent(s) in the solvent system may decrease, the solubility may decrease more slowly than the L / G ratio increases. In such an example, it may be possible to prioritize the L / G ratio over solubility to increase the throughput of the process.

[0058] In yet other examples, the concentration of the active pharmaceutical ingredient may be limited by the viscosity and by the maximum allowable excipient concentration in the solvent system for spray drying. In such examples, the ratio of the low volatility solvent(s) in the solvent system can be set to the minimum level that allows for the highest drug concentration, which may maximize the spray drying mass ratio. For example, even if increasing the ratio of the low volatility solvent(s) further increases the solubility of the material to be spray dried, there may be no advantage in using a higher ratio of low volatility solvent(s) than that which allows for the maximum allowable excipient concentration in the solvent system.

[0059] Accordingly, multiple solvent blends with various ratios of low volatility solvent(s) and high volatility solvent(s) can be considered. When the solubilities of multiple candidate solvent blends are comparable, DMSO may be preferentially selected as the low volatility solvent, as discussed above. For example, a first solvent system containing DMSO as the low volatility solvent can be selected when the drug solubility is similar in the first solvent system compared to a second solvent system containing a different low volatility solvent (e.g., one that does not contain DMSO). Further, when multiple ratios of low volatility solvent(s) result in comparable solubilities, the high volatility solvent(s) can be selected at the lowest ratio because they can be easily removed by spray drying. As used herein, the term "comparable" may mean substantially the same solubility value. As another example, the term "comparable" may mean solubility values within a threshold ratio of each other, e.g., within 1 - 20%.

[0060] At 804, method 800 includes selecting a process outlet temperature and a spray-drying mass ratio based on the predicted glass transition temperature of the material to be spray-dried according to the processing mass ratio of the material to be spray-dried and the temperature sensitivity of the material to be spray-dried. For example, the selected process outlet temperature may not be higher than the predicted glass transition temperature of the material spray-dried at a given spray-drying mass ratio. In some examples, the selected process outlet temperature may be lowered from the predicted glass transition temperature to allow for variations in the process outlet temperature that may occur during spray-drying and / or due to the temperature sensitivity of the material to be spray-dried. In such examples, the selected process outlet temperature may be placed at the center of the predicted variations to ensure that any temperature fluctuations during spray-drying do not cause the process outlet temperature to exceed the predicted glass transition temperature or the decomposition temperature of the material.

[0061] At 806, method 800 includes preparing a solvent system according to the selected low volatility solvent(s), the selected high volatility solvent(s), and the selected ratio of the low volatility solvent(s) to the high volatility solvent(s) (e.g., the ratio determined at 802). The solvent system can be prepared on a relatively large scale. For example, since it may be desirable to process at least 1 kilogram (kg) of drug, a solvent system sufficient to dissolve 1 kg of drug in solution can be prepared. For example, the amount of the solvent system to be prepared can be estimated based on the solubility study described above at 802.

[0062] At 808, method 800 includes adding a drug and excipient(s) to the solvent system to form a solution. The solution may be stirred to aid mixing. In some examples, method 800 includes heating the solution to increase solubility, as optionally indicated at 810. For example, the heating temperature can be maintained below the boiling point of the solvent system and below the decomposition temperature of the drug and excipient(s).

[0063] In 812, method 800 includes spray drying a solution at a selected spray drying mass ratio and a selected process outlet temperature to form a dried amorphous dispersion. As described above with respect to FIG. 1, the solution is pumped through a spray nozzle of a spray dryer at a liquid feed rate of the selected spray drying mass ratio, and the spray nozzle converts the solution into droplets of a small size (e.g., from microns to hundreds of microns) and contacts it with a heated drying gas supplied to the spray dryer at a gas feed rate of the selected spray drying mass ratio.

[0064] During spray drying, method 800 includes operating the spray dryer at a process outlet temperature lower than the predicted glass transition temperature of the material (e.g., an upper threshold process outlet temperature), as shown at 814. The upper threshold process outlet temperature may be based on the chemical and physical stability constraints of the material. As defined above at 804, operating below the predicted glass transition temperature may reduce the physical instability (e.g., crystallization and / or phase separation) of the spray-dried product. Further, in some systems, operating below the predicted glass transition temperature may also reduce the chemical decomposition of the spray-dried product.

[0065] Thereafter, method 800 may end. For example, method 800 may be repeated for each pharmaceutical formulation to spray dry the pharmaceutical formulation using optimized process parameters. Further, the spray-dried amorphous dispersion may be further dried via secondary drying techniques such as tray drying or vacuum drying.

[0066] Methods 700 and 800 may be applied to spray dry multiple combinations of low volatility solvents, high volatility solvents, drugs, and excipients. Examples of possible combinations and the yields obtained are shown in Table 1 below. The spray-dried products collected for each example shown in Table 1 were characterized as having an amorphous free-flowability.

[0067]

Table 1

[0068] It was a powder and no significant accumulation on the spray dryer was observed. Table 1. Spray drying parameters and results when following Methods 700 and 800. VF is vemurafenib, SL is spironolactone, FS is furosemide, and HT is hydrochlorothiazide. As shown in Table 1, a plurality of drugs, excipients, and low-volatility solids can be used according to Methods 700 and 800 to produce spray-dried dispersions with a yield of at least 50%. In the example where dBET1 is the drug, by increasing the solubility by including up to 25% DMSO, spray drying of 100% drug dispersions becomes possible. In such an example, a yield of 42% was achieved with a relatively small batch size of 1 g. Furthermore, Table 1 shows two examples: one of spray drying hydrochlorothiazide using DMSO as a low-volatility solvent, and another of keeping the spray drying parameters constant and replacing DMSO with DMF. Comparing the two examples, it can be seen that when replacing DMSO with the more volatile (such as having a higher vapor pressure) DMF, the yield increases from 55% to 78%.

[0069] Conversely, as shown in Methods 700 and 800, if the spray drying mass ratio and the outlet process temperature are selected beyond the maximum spray drying mass ratio and the outlet temperature, a sticky, wet, and non-free-flowing product is obtained, and as shown in Table 2 below, the product yield may decrease.

[0070]

Table 2

[0071] As an example, as shown in Table 2, the 0.0150 L / G selected for the spray drying of the vemurafenib formulation is greater than the maximum spray drying mass ratio. Products obtained from spray drying and L / G ratios exceeding the maximum spray drying ratio may be wet, sticky, and not free-flowing. Such products may adhere inside the spray dryer, and the product yield may decrease.

[0072] Referring now to FIG. 9, exemplary process map 900 shows the conditions for spray drying a material with respect to the advantages regarding increases in both throughput and yield. As the process conditions become unfavorable or undesirable, such as due to a decrease in throughput and / or yield, the intensity of the shading (e.g., darkness) increases. The vertical axis of process map 900 represents the L / G ratio, and the horizontal axis represents the outlet temperature.

[0073] Even when the throughput is high due to a high L / G ratio, spray drying at an outlet temperature higher than the glass transition temperature of the material at a given L / G ratio may result in a decrease in yield. For example, an equivalent plot where the outlet temperature is equal to the glass transition temperature may define at least a part of the upper boundary of the brightest (e.g., least shaded) region 902 having the highest advantages with respect to both throughput and yield. Further, as indicated by the increase in shading at higher L / G ratios, the advantages may decrease when the L / G ratio is higher than the equivalent plot. As another example, as the outlet temperature increases due to the chemical and / or physical instability of the material as the outlet temperature rises, the advantages generally decrease, and thus the shading may become stronger. Although the yield may not be affected, as can be seen from the fact that the shading intensity increases as the L / G ratio decreases, when the L / G ratio decreases due to a decrease in throughput, the advantages generally decrease.

[0074] In this way, combining a low-volatility solvent with a high-volatility solvent may achieve a significant increase in drug solubility and make the process economically feasible on a commercial scale. By using a mixture of a low-volatility solvent and a high-volatility solvent at an optimal ratio and process temperature, the technical effect of increasing the solubility of the drug in the solution treated by spray drying may increase the yield and quality of the obtained spray-dried dispersion of the drug (e.g., the solvent level is below the threshold and is not physically or chemically decomposed).

[0075] The present disclosure provides support for a method of preparing a dispersion of a pharmaceutical formulation, the method comprising selecting a solvent mixture comprising a first proportion of a low volatility solvent and a second proportion of a high volatility solvent based on the solubility of the drug of the pharmaceutical formulation in the solvent mixture, forming a solution of the pharmaceutical agent in the solvent mixture, and using a spray drying mass ratio to spray dry the solution to form a dispersion, wherein the spray drying mass ratio is selected based on the relationship between the glass transition temperature of the pharmaceutical formulation and the relative saturation of the low volatility solvent during spray drying, the spray drying mass ratio defines the liquid feed rate of the solution relative to the gas feed rate of the drying gas during spray drying, and using a process outlet temperature lower than the glass transition temperature of the pharmaceutical formulation. In a first example of this method, the spray drying mass ratio is further selected to maximize the throughput of the pharmaceutical formulation while spray drying the solution at a process outlet temperature below the glass transition temperature, and the glass transition temperature varies depending on the spray drying mass ratio. In a second example of the method, optionally including the first example, the first proportion is at least 10%, and the selection of the solvent mixture is further based on the kinetic and thermodynamic properties of removing the solvent mixture via spray drying. In a third example of the method, optionally including one or both of the first and second examples, the pharmaceutical formulation further comprises an excipient, the excipient is included in the solution of the solvent mixture, and comprises at least one of hypromellose acetate succinate, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, and polymethacrylate, and the solvent mixture comprises at least one of dimethyl sulfoxide (DMSO), n-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF), and n,n-dimethylacetamide (DMAC). In a fourth example of the method, optionally including one or more or each of the first to third examples, dimethyl sulfoxide (DMSO) is selected as the low volatility solvent based on the solubility of the drug that is equivalent between a solvent blend containing DMSO and a solvent blend not containing DMSO, and the spray drying mass ratio is greater than a lower threshold spray drying mass ratio determined based on the process outlet temperature.In a fifth example of this method, it optionally includes one or more or each of the first to fourth examples, and when the process outlet temperature is 60 °C or higher, the lower threshold spray drying mass ratio is 0.004 with respect to DMSO, and when the process outlet temperature is less than 60 °C, the lower threshold spray drying mass ratio is 0.001 with respect to DMSO. In a sixth example of this method, it optionally includes one or more or each of the first to fifth examples, and the process outlet temperature is less than the upper threshold process outlet temperature determined based on the constraints of the chemical and physical stability of the pharmaceutical preparation. In a seventh example of this method, it optionally includes one or more or each of the first to sixth examples, and the upper threshold process outlet temperature is 90 °C.

[0076] The present disclosure also provides support for a method for identifying process parameters for spray drying a pharmaceutical formulation from a low volatility solvent, the method comprising generating a process map associating the process outlet temperature of the spray drying with the spray drying mass ratio based on the glass transition of the pharmaceutical formulation at each spray drying mass ratio, and generating an equivalence plot on the process map in which the glass transition temperature of the pharmaceutical formulation is equal to the process outlet temperature corresponding to the spray drying mass ratio. In a first example of the method, generating a process map associating the process outlet temperature of the spray drying with the spray drying mass ratio based on the glass transition temperature of the pharmaceutical formulation at each spray drying mass ratio comprises determining a first relationship between the relative saturation of the low volatility solvent and the glass transition temperature of the pharmaceutical formulation, determining a second relationship between the spray drying mass ratio and the relative saturation of the low volatility solvent at a given process outlet temperature of the spray drying based on the first relationship, and determining the glass transition temperature of the pharmaceutical formulation at each spray drying mass ratio based on the second relationship. In a second example of the method, optionally including the first example, the method further comprises identifying the maximum value of the equivalence plot corresponding to the maximum spray drying mass ratio of the equivalence plot, and identifying the corresponding process outlet temperature at the equivalence plot maximum value. In a third example of the method, optionally including one or both of the first and second examples, the method further comprises selecting the maximum spray drying mass ratio and a process outlet temperature below the corresponding process outlet temperature at the maximum value of the equivalence plot as process parameters for spray drying the pharmaceutical formulation. In a fourth example of the method, optionally including one or more or each of the first to third examples, the method further comprises selecting a portion of the low volatility solvent that is lower than the highest portion of the low volatility solvent based on at least one of the solubility of the pharmaceutical formulation in the low volatility solvent, the viscosity of the pharmaceutical formulation in the low volatility solvent, and the temperature sensitivity of the pharmaceutical formulation. In a fifth example of the method, optionally including one or more or each of the first to fourth examples, the equivalence plot defines the maximum spray drying mass ratio as a function of the process outlet temperature of the spray drying.

[0077] The present disclosure also provides support for a system for preparing a pharmaceutical formulation, the system comprising a solution of a drug and an excipient dissolved in a solvent blend comprising at least one low volatility solvent and at least one high volatility solvent, wherein the at least one low volatility solvent is at least 10% of the solvent blend, and a spray dryer configured to receive a flow of the solution and a drying gas and produce a dry dispersion of the drug and the excipient as a pharmaceutical formulation, wherein the process outlet temperature of the spray dryer is selected according to the spray drying mass ratio of the liquid feed rate of the solution to the gas feed rate of the drying gas. In a first example of the present system, the at least one low volatility solvent is selected from dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF), and N,N-dimethylacetamide (DMAC), and wherein the at least one high volatility solvent is selected from acetone, methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran, methylene chloride, N-methyltetrahydrofuran, n-propanol, chloroform, hexane, acetic acid, cyclohexane, ethyl ether, and water. In a second example of the present system, optionally including the first example, the process outlet temperature of the spray dryer is lower than the glass transition temperature of the dry dispersion of the drug and the excipient. In a third example of the present system, optionally including one or both of the first and second examples, the relative saturation of the at least one low volatility solvent at the outlet of the spray dryer in the equilibrium state is 5 to 50%. In a fourth example of the present system, optionally including one or more or each of the first to third examples, the spray drying mass ratio of the liquid feed rate of the solution to the gas feed rate of the drying gas is selected to maximize the amount of the drug and the excipient processed per unit time. In a fifth example of the present system, optionally including one or more or each of the first to fourth examples, the solvent blend is selected according to the solubility of the drug and the excipient in the solvent blend and the maximum spray drying mass ratio of the liquid feed rate of the solution to the drying gas using the solvent blend.

[0078] In an alternative embodiment, the present disclosure also provides a support for a pharmaceutical formulation spray dried by the following process: forming a solution of the active pharmaceutical ingredient and excipients of the pharmaceutical formulation in a solvent system comprising a low volatility solvent, where the solvent system is selected based on the solubility of the active pharmaceutical ingredient in the low volatility solvent, and the kinetic and thermodynamic properties for removing the low volatility solvent during spray drying, and spray drying the solution using a spray drying mass ratio, where the spray drying mass ratio is selected based on the relationship between the glass transition temperature of the pharmaceutical formulation and the relative saturation of the low volatility solvent during spray drying, where the spray drying mass ratio defines the liquid feed rate of the solution relative to the gas feed rate of the drying gas during spray drying, and the process outlet temperature is below the glass transition temperature of the pharmaceutical formulation. In a first example of the system, while spray drying the solution at a process outlet temperature below the glass transition temperature, the spray drying mass ratio used during spray drying of the pharmaceutical formulation is further selected to maximize the processing throughput of the pharmaceutical formulation, and the glass transition temperature varies depending on the spray drying mass ratio. In a second example of the system, optionally including the first example, the low volatility solvent is at least 10% of the solvent system. In a third example of the system, optionally including one or both of the first and second examples, the low volatility solvent includes dimethyl sulfoxide (DMSO). In a fourth example of the system, optionally including one or more or each of the first to third examples, the excipient includes at least one of hypromellose acetate succinate, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, and polymethacrylate. In a fifth example of the system, optionally including one or more or each of the first to fourth examples, the low volatility solvent further includes at least one of n-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF), and n,n-dimethylacetamide (DMAC), and the solvent system further includes at least one of acetone, methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran, methylene chloride, n-methyltetrahydrofuran, n-propanol, chloroform, hexane, acetic acid, cyclohexane, ethyl ether, and water.

[0079] The following claims particularly point out certain combinations and sub - combinations that are regarded as new and non - obvious. These claims may refer to "one" element or "a first" element or its equivalents. Such claims should be understood to include the incorporation of one or more such elements and do not require or exclude two or more such elements. Other combinations and sub - combinations of the disclosed features, functions, elements, and / or characteristics may be claimed through amendment of these claims or through the presentation of new claims in this application or related applications. Such claims are considered to be within the scope of the present disclosure, whether broader, narrower, equal to, or different from the original claims.

Claims

1. A method for preparing a dispersion of a pharmaceutical preparation, comprising: selecting a solvent mixture comprising a first proportion of a low-volatility solvent and a second proportion of a high-volatility solvent based on the solubility of the drug of the pharmaceutical preparation in the solvent mixture; forming a solution of the drug of the pharmaceutical preparation in the solvent mixture; spray-drying the solution using a spray-drying mass ratio to form the dispersion, wherein the spray-drying mass ratio is selected based on the relationship between the glass transition temperature of the pharmaceutical preparation and the relative saturation of the low-volatility solvent during spray-drying, the spray-drying mass ratio defines the ratio of the liquid feed rate of the solution to the gas feed rate of the drying gas during spray-drying, and using a process outlet temperature lower than the glass transition temperature of the pharmaceutical preparation;

2. The method according to claim 1, wherein the spray-drying mass ratio is further selected to maximize the processing throughput of the pharmaceutical preparation while spray-drying the solution at the process outlet temperature below the glass transition temperature, and the glass transition temperature varies according to the spray-drying mass ratio.

3. The method according to claim 1 or 2, wherein the first proportion is at least 10%, and the selection of the solvent mixture is further based on the kinetic and thermodynamic properties of the removal of the solvent mixture via spray-drying.

4. The pharmaceutical preparation further comprises an excipient, the excipient is contained in the solution of the solvent mixture, and comprises at least one of hypromellose acetate succinate, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, and polymethacrylate, and the solvent mixture comprises at least one of dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF), and N,N-dimethylacetamide (DMAC). The method according to any one of claims 1 to 3.

5. Dimethyl sulfoxide (DMSO) is selected as the low-volatility solvent based on the solubility of the drug that is equivalent between a solvent blend containing DMSO and a solvent blend not containing DMSO, and the spray-drying mass ratio is greater than a lower threshold spray-drying mass ratio determined based on the process outlet temperature. The method according to any one of claims 1 to 4.

6. The method according to claim 5, wherein when the process outlet temperature is 60 °C or higher, the lower threshold spray drying mass ratio is 0.004 with respect to DMSO, and when the process outlet temperature is less than 60 °C, the lower threshold spray drying mass ratio is 0.001 with respect to DMSO.

7. The method according to any one of claims 1 to 6, wherein the process outlet temperature is less than an upper threshold process outlet temperature determined based on constraints on the chemical and physical stability of the pharmaceutical formulation.

8. The method according to claim 7, wherein the upper threshold process outlet temperature is 90 °C.

9. A method for specifying process parameters for spray drying a pharmaceutical formulation from a low volatility solvent, comprising: generating a process map associating the process outlet temperature of the spray drying with the spray drying mass ratio based on the glass transition temperature of the pharmaceutical formulation at each spray drying mass ratio; generating, on the process map, an equivalent plot in which the glass transition temperature of the pharmaceutical formulation is equal to the process outlet temperature corresponding to the spray drying mass ratio.

10. Generating the process map associating the process outlet temperature of the spray drying with the spray drying mass ratio based on the glass transition temperature of the pharmaceutical formulation at each spray drying mass ratio comprises: determining a first relationship between the relative saturation of the low volatility solvent and the glass transition temperature of the pharmaceutical formulation; determining a second relationship between the spray drying mass ratio and the relative saturation of the low volatility solvent at a given process outlet temperature of the spray drying based on the first relationship; determining the glass transition temperature of the pharmaceutical formulation at each spray drying mass ratio based on the second relationship. The method according to claim 9.

11. further comprising identifying the maximum value of the equivalent plot corresponding to the maximum spray drying mass ratio of the equivalent plot; identifying the corresponding process outlet temperature at the maximum value of the equivalent plot. The method according to claim 9 or 10.

12. The method according to claim 11, further comprising selecting the maximum spray drying mass ratio and a process outlet temperature below the corresponding process outlet temperature at the maximum value of the equivalent plot as the process parameters for spray drying the pharmaceutical formulation.

13. The method according to claim 11 or 12, further comprising selecting a portion of the low volatility solvent that is lower than the highest portion of the low volatility solvent based on at least one of solubility of the pharmaceutical formulation in the low volatility solvent, viscosity of the pharmaceutical formulation in the low volatility solvent, and temperature sensitivity of the pharmaceutical formulation.

14. The method according to any one of claims 9 to 12, wherein the equivalent plot defines a maximum spray drying mass ratio according to the process outlet temperature of the spray drying.

15. A system for preparing a pharmaceutical formulation, A solution of a drug and an excipient dissolved in a solvent blend comprising at least one low volatility solvent and at least one high volatility solvent, wherein the at least one low volatility solvent is at least 10% of the solvent blend, and A spray dryer configured to receive the solution and a stream of drying gas and produce a dry dispersion of the drug and the excipient as the pharmaceutical formulation, wherein the process outlet temperature of the spray dryer is selected according to a spray drying mass ratio of the liquid supply rate of the solution to the gas supply rate of the drying gas. A system comprising a spray dryer.

16. The system according to claim 15, wherein the at least one low volatility solvent is selected from dimethyl sulfoxide (DMSO), n-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF), and n,n-dimethylacetamide (DMAC), and the at least one high volatility solvent is selected from acetone, methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran, methylene chloride, n-methyltetrahydrofuran, n-propanol, chloroform, hexane, acetic acid, cyclohexane, ethyl ether, and water.

17. The system according to claim 15 or 16, wherein the process outlet temperature of the spray dryer is less than the glass transition temperature of the dry dispersion of the drug and the excipient.

18. The system according to any one of claims 15 to 17, wherein the relative saturation of the at least one low volatility solvent at the outlet of the spray dryer in an equilibrium state is 5 to 50%.

19. The spray drying mass ratio of the liquid supply rate of the solution to the gas supply rate of the drying gas is selected to maximize the amount of the drug and the excipient processed per unit time, for the system according to any one of claims 15 to 18.

20. The solvent blend is selected according to the solubility of the drug and the excipient in the solvent blend, and the maximum spray drying mass ratio of the liquid supply rate of the solution to the drying gas using the solvent blend, for the system according to any one of claims 15 to 19.

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