Article pubs.acs.org/OPRD
Preparation of the HIV Attachment Inhibitor BMS-663068. Part 9. Active Pharmaceutical Ingredient Process Development and Powder Properties Thomas E. La Cruz,*,† Eric M. Saurer,*,† Joshua Engstrom,‡ Michael S. Bultman,† Robert Forest,† Fulya Akpinar,† Glenn Ferreira,† Jeanne W. Ho,† Masano Huang,† Michelle Soltani,† Saravanababu Murugesan,† Dayne Fanfair,† Antonio Ramirez,† Victor W. Rosso,† Deniz Erdemir,‡ Tamar Rosenbaum,‡ Michelle Haslam,† Stephen Grier,∥ Michael Peddicord,† Charles Pathirana,† Jonathan Marshall,† Wei Ding,† Yande Huang,† Sloan Ayers,† Alan Braem,† Richard L. Schild,† Sabrina E. Ivy,† Joseph Payack,† Douglas D. McLeod,§ Whitney Nikitczuk,§ Wendel Doubleday,† Sapna Shah,∥ and David A. Conlon† †
Chemical and Synthetic Development, ‡Drug Product Science and Technology, §API Operations, ∥Analytical and Bioanalytical Operations, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903-0191, United States ABSTRACT: This final communication, of a nine part publication series, details the process development history for the final synthetic step to prepare the drug substance BMS-663068 tris(hydroxymethyl)aminomethane (TRIS) salt. The challenge of developing a robust commercial process to prepare BMS-663068-TRIS salt (active pharmaceutical ingredient, API) was achieved by studying the underlying mechanisms that governed key processing characteristics. Eliminating a slurry-to-slurry transformation results in predictable reaction kinetics and control of impurity formation. Key powder property aspects, such as specific surface area and bulk density, were controlled by examining the impact of seed age, crystallization relative supersaturation (RSS), and particle attrition due to agitation during drying. Ultimately, the processing parameters established for preparation of this drug substance resulted in the generation of the target compound with consistent quality, powder properties, and yield across multiple batches.
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INTRODUCTION The global acquired immune deficiency syndrome (AIDS) epidemic, caused by the human immunodeficiency virus-1 (HIV-1), has spurred development of several multiclass antiretroviral therapies over the past three decades.1 Despite these advances, millions of new infections and deaths are reported each year in addition to the millions of people living with this disease.2 The emergence of HIV-1 viral strains resistant to standard therapies, coupled with the need to improve longer term drug tolerability, drove the pursuit and ultimate discovery of novel mechanisms of action to combat the HIV-1 virus. This led to the genesis of attachment inhibitors as therapeutic agents: compounds that operate by interfering with the virus’ initial entry into a host cell.3 BMS-626529 (6) is a new antiretroviral compound that targets the gp120 glycoprotein on the HIV-1 surface and prevents binding to the CD4 cellular receptor necessary for infection of a target cell. Although promising results were observed early in development, BMS-626529 exhibited low solubility leading to limited bioavailability. This challenge was addressed by engineering a phosphate motif anchored by a methylene group onto the BMS-626529 N-1 of the azaindole core. The resulting phosphonoxymethyl prodrug, BMS-663068, has vastly improved solubility characteristics and addressed the bioavailability challenges associated with the parent molecule and was designated as the program’s principal active pharmaceutical ingredient (API).4 © XXXX American Chemical Society
The previous eight manuscripts of this nine-part publication series describe the synthesis, process development challenges, and solutions leading up to preparation of penultimate intermediate, compound 1 (Scheme 1). This final communication details the process development history for the final synthetic step to prepare the drug substance BMS-663068tris(hydroxymethyl)aminomethane (TRIS) salt (4). Developing a robust API process (the ability to achieve acceptable quality while tolerating variability in input quality and process parameters) is a resource intensive challenge. Controlling process- and input-related impurities, understanding the reaction rates and mechanism, achieving the desired crystal form, and mitigating the impact of crystallization and drying parameters on powder properties are of paramount importance when developing an API step. BMS-663068 was no exception; several challenges were encountered during development of the chemical process to prepare this compound. Herein, we describe some of these challenges and how they were addressed to achieve the goal of defining a robust, commercially scalable process. Special Issue: From Invention to Commercial Process Definition: The Story of the HIV Attachment Inhibitor BMS-663068 Received: April 5, 2017
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DOI: 10.1021/acs.oprd.7b00138 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Scheme 1. BMS-663068 Reaction
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PROCESS OVERVIEW The chemical process to produce BMS-663068 went through several iterations from its initial inception to a process worthy of manufacturing scale. Starting in the early development phase, a principal focus was placed on limiting unit operations, such as work-ups, distillation, and solvent exchanges. Due to the nature of this molecule, the process could only be developed within certain confines. Namely, it was necessary to include water, acetone, and TRIS as they were essential to generate the desired crystal form. Limiting reagent and solvent selection posed a challenge to development activities especially when the impurity profile of earlier intermediates was not well-defined. A process overview is depicted in Figure 1. After the reaction is
complete, the reaction stream is treated with TRIS, and the solution is then polish-filtered; the product was crystallized from acetone, filtered, washed, and dried under heat and vacuum.
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CHEMISTRY The chemical transformation to prepare BMS-663068 is a solvolysis reaction of the two tert-butyl groups from the phosphate moiety within compound 1 (Scheme 1).5 Superficially, the reaction is operationally simple requiring a polar solvent and acid catalyst that can come from either an external source or be generated in situ. The latter strategy, which removes the first tert-butyl group and exposes the phosphoric acid functionality, was chosen for early compound deliveries due to its operational simplicity.6 Thus, the initial conditions involved heating compound 1 to 50 °C in a mixture of acetone and water (3:2 v/v) resulting in the facile removal of the labile first tert-butyl group within the first 2 h and formation of intermediate phosphate monoester 2. The consumption of this intermediate was rate-limiting. Continued heating for an 8−10 h period resulted in almost complete conversion to BMS663068-acid 3. The process stream was then treated with one equivalent of TRIS and crystallized with acetone to give the desired BMS-663068-TRIS salt 4. Acetone, water and TRIS were essential for the genesis of the desired crystalline BMS-
Figure 1. BMS-663068 process overview.
Scheme 2. Impurities in BMS-663068 Process
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DOI: 10.1021/acs.oprd.7b00138 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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solid, slurry, and supernatant components by HPLC and in-line FT-IR revealed an important reaction detail (Figure 2). When
663068 form; thus, any BMS-663068 process required the inclusion of these three chemical components (vide infra).7 Several challenges were identified during early development of this transformation. First, although approximately 75% of the tert-butyl group mass from compound 1 was converted to tBuOH due to the presence of water, the remainder (∼0.5 equiv) formed isobutylene and resulted in off-gassing from the process stream.8 Isobutylene off-gassing occurred early in the reaction as intermediate 2 was being generated. The bulk of isobutylene formed quickly during the first 0.5 h of the reaction, with a maximum off-gassing rate of 0.2 L-min/kg achieved within 15 min. Off-gassing quickly decreased once the desired temperature was reached and compound 1 was completely dissolved. A small amount of isobutylene was liberated throughout the reaction as phosphate monoester intermediate 2 was consumed. A thermal oxidizer was used to control isobutylene emissions at the pilot plant scale. The amount and maximum rate of off-gassing from the acetone/water reaction stream were within the capability of the thermal oxidizer used at the pilot plant scale, but a further reduction in the amount and rate of off-gassing was desirable to provide improved flexibility for long-term manufacturing. A number of azaindole-related byproducts were identified in addition to the reaction intermediate, phosphate monoester 2 (Scheme 2). A consequence of using water as a cosolvent and tbutyl cation scavenger was the hydrolysis of the benzoyl amide under the acidic reaction conditions at 50 °C, resulting in the formation of impurity 5. Control of impurity 5 was paramount as the final crystallization in 90:10 acetone−water (v/v) purged only ∼0.1 LCAP (liquid chromatography area percent) due to its low solubility (100 mg/mL solubility in the same solvent system) precipitated as well, either by cocrystallization or entrainment within the BMS-663068 solid matrix. Significantly higher levels of intermediate 2 were observed in the solids sampled from the reaction mixture than in the supernatant (squares vs circles in Figure 2). This difference between the solid and the supernatant concentrations of intermediate 2 complicated the determination of the reaction end point, due to the difficulty in sampling a representative ratio of solid and supernatant. These studies also revealed that the concentrations of intermediate 2 in the BMS-663068-acid solid and supernatant samples were not consistent from experiment to experiment (dashed blue line vs dashed green line, Figure 2), and that the time at which the reaction formed a slurry was variable from batch to batch (2−5 h into reaction age). This variability resulted in a large time window (9−12 h) required to complete the solvolysis reaction, since the consumption of intermediate 2 became mass transfer limited. Transformations that generate slurries can have scale-dependent reaction rates and are known to introduce complications to a given process.11 Furthermore, the complicated and unpredictable reaction rate made it difficult to control formation of impurities such as hydrolysis product 5. Lowering the batch temperature to below 50 °C resulted in a reduced rate of BMS-663068 degradation but also caused incomplete consumption of intermediate 2 and impacted the overall reaction yield. Although this process was successfully executed on the pilot scale, challenges such as the poor control of degradation products, isobutylene off-gassing, unpredictable reaction kinetics, formation of thick slurries, variable particle sizes, and bulk density of the BMS-663068-TRIS salt crystals (vide infra), ultimately made the acetone−water reaction solvent system unsuitable for commercial-scale manufacturing. To improve the BMS-663068 process for large-scale manufacturing, the focus was first centered on examining the reaction parameters that would result in a homogeneous solvolysis process stream. In particular, a solvent system where the BMS-663068-acid demonstrates high solubility was sought to achieve a homogeneous reaction and maximize product throughput. To identify an appropriate system, the solubilities of the BMS-663068 step reaction components were screened in a broad range of solvents (summarized in Scheme 3). The solubility of input material 1 in polar organic solvents was C
DOI: 10.1021/acs.oprd.7b00138 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Scheme 3. Solubility Study of API Reaction Components
Figure 3. BMS-663068-acid solubility for various ratios of AcOH−water.
sufficiently different from the phosphoric acid group within BMS-663068-acid (pKa1 2.6), which could have an impact on the BMS-663068-TRIS salt formation and their boiling points raised concerns regarding their removal during the isolation and drying operations.16 After exploring key reaction parameters, such as solvent− cosolvent ratios, concentration, and temperature, a set of processing conditions centered on an acetic acid−water system were identified for the solvolysis reaction. Acetic acid (AcOH), a Class 3 solvent with a pKa value of 4.76, solubilized BMS663068-acid (∼30 mg/mL) and its process-related byproducts. When water, the desired cosolvent, and tert-butyl cation scavenger of choice was mixed with AcOH, the solubility of 3 dramatically increased (Figure 3). The solubility of 3 reached a maximum value of >400 mg/mL at a 2:1 AcOH−water (v/v) ratio. A solvent system that results in a homogeneous reaction was identified, and at this stage the attention was focused on optimizing the reaction concentration with an emphasis on
excellent, but the utility of these solvents was limited by the poor solubility of BMS-663068-acid. Water-miscible Class 2 solvents such as dimethylformamide, dimethylamine, and Nmethyl-2-pyrrolidone had the desired solvation characteristics, but their low volatility could impact API quality if not adequately removed during isolation and drying.12 DMSO, a Class 3 solvent, was also considered for its powerful solvation characteristics (>100 mg/mL of BMS-663068-acid), but again its low volatility and reactivity toward electrophiles introduced undesirable risk to the API’s impurity profile.13 Carboxylic acids, classical reagents for Boc group removal, were evaluated for BMS-663068-acid preparation.14 Acids with pKa values equal to or lower than trifluoroacetic acid (TFA, pKa 0.2) rapidly cleaved the prodrug motif to give compound 6 under anhydrous conditions. When water was introduced as a cosolvent, the hydrolysis of the acid-sensitive benzoyl amide ensued, forming compound 5.15 Other organic acids (glyoxylic, glycolic, pyruvic, propionic) had the desired solvation qualities when mixed with water, but their pKa values were not D
DOI: 10.1021/acs.oprd.7b00138 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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and 9 (0.18 mg/mL solubility) were controlled by setting specified limits of their related parent compounds in input 1. Three acid sensitive functional groups resided within compound 1 (tert-butyl phosphate ester, phosphohemiaminal ether, benzoylamide), and it was important to quantitatively understand the chemoselectivity of the reaction. This was accomplished by measuring the rate of formation for compounds 5 and 6 and degradation of 8 under the BMS663068 reaction conditions and then comparing the activation energies for those transformations. Interestingly, the activation energy (EA) for the hydrolysis of the benzoyl group was calculated to be comparable to EA for tert-butyl group cleavage within experimental error (EA ∼ 22 kcal/mol), supporting the inherent tendency of impurity 5 to form in the presence of water regardless of reaction temperature. The phosphohemiaminal group was more resistant to hydrolytic degradation (EA ∼ 27 kcal/mol) when compared to both the phosphate ester and benzoyl amide stability. It was expected that compound 8, having a second appended methylene phosphoryl group, would readily degrade under the BMS-663068 reaction conditions, but the converse was observed, and its resistance to undergo hydrolytic decomposition matched its calculated EA (∼31 kcal/mol). This result underlined the importance of setting specified limits of its parent compound in input 1 to ensure the impurity profile integrity of BMS-663068. Lastly, a stability trend could be assigned to the labile structural motifs: tert-butyl ∼ benzoyl amide < phosphohemiaminal. The solvolysis reaction of 1 in AcOH−water proved to be superior to the acetone−water process in terms of impurity formation and purge, material throughput, reaction rates, and isobutylene off-gassing. Having defined a robust solvolysis, the focus shifted to developing a robust crystallization protocol for the desired form of the BMS-663068-TRIS salt. To confirm that modifying the reaction solvent system from acetone−water to AcOH−water did not impact the yield of BMS-663068-TRIS salt, the solubility of the final product was measured at the crystallization end point (Table 1) at varying
maximizing material throughput and designing a high-yielding crystallization. The solubility data presented in Figure 3 illustrate that 2:1 AcOH−water (v/v) at a concentration of 2.5−3.0 L/kg of BMS-663068-acid was optimal to maintain full dissolution throughout the reaction. In addition, the solubility of the BMS663068-TRIS salt in this solvent composition was quite high, implying precipitation of the final salt 4 before crystallization was not a concern. Another benefit of the AcOH−water solvent system was that solvolysis of the tert-butyl groups from starting material 1 began to take place as soon as the input material was introduced to the solvent mixture. This enhanced reaction rate, enabled by the presence of AcOH, allowed for the transformation to be executed at a lower temperature (35 °C) than in the previous acetone−water process (50 °C). The homogeneous reaction conditions consistently reached completion within 10−11 h at temperature, regardless of the reaction scale (1 g−100 kg), and intermediate 2 was almost entirely consumed (
