Solubility of progesterone in supercritical carbon dioxide and its micronization through RESS

22 Nov.,2022

 

Progesterone Powder

Particle engineering has been becoming a very important issue in the field of pharmaceutical solid dosage forms and size reduction is the most frequently proposed method to ensure high performance of pharmaceutical particles involved. Thus particle size reduction to nano- or micro-size is then gaining ever-increasing concerns as this can have a great impact on the biopharmaceutical behaviors such as solubility, dissolution rate, and bioavailability of the drug, especially for injectable drug products and for the administration by the inhalatory route. Recently, particle size reduction by means of techniques based on supercritical carbon dioxide (SCCO2), such as particles from gas-saturated solutions/suspensions (PGSS) [1], [2], supercritical fluid-assisted atomization (SAA) [1], [2], supercritical antisolvent processes (SAS) [1], [3], [4], [5], and rapid expansion of supercritical solution (RESS) [1], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], has attracted particular attention for those thermally unstable substances like pharmaceutics or explosives that may be difficult to comminute. SCCO2 can be used as a solvent [1], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], an anti-solvent [1], [3], [4], [5], a solute [1], a co-solute [1] or a co-solvent [1] for the drug to be recrystallized, due to its low critical temperature, low cost, availability at high purity, and excellent safety properties. Of all, the RESS particle formation technique may be, perhaps, considered the simplest process for producing solvent-free fine particles having a narrow particle size distribution [1], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36].

In the RESS process, the drug to be comminuted is usually dissolved in a SCCO2 at a desired high pressure and temperature and then the supercritical drug/CO2 solution is rapidly sprayed through a well-designed nozzle to ambient conditions. Due to the great pressure drop in a short time, the decrease in density renders the solvating strength of CO2 to the drug being suddenly lost and the dissolved solute becomes insoluble. This subsequently brings very high solute supersaturation, and leads to fast nucleation and uniform crystal growth which hence enables the production of solvent-free fine drug particles with a narrow size distribution. The most outstanding characteristic of particle formation through RESS methodology is the possibility of obtaining solids with unique morphology and small size for a wide range of materials. Obviously, adequate yield by means of this technique can be applied only to drugs having ‘high’ solute solubility in SCCO2, at least, of the order of 10−   4 mole fraction. Thus several recent studies have highlighted that the drug solubility in SCCO2 is critical to the RESS micronization method as the solubility affects the supersaturation of the drug in the solvent as well as the mass transfer of the drug-loaded solution [28], [29], [30]. Moreover, Kim et al. [28] have reported that the particle diameter of ultra-fine drug particles resulted from the RESS process is found to decrease with the increase in the solubility for lidocaine, griseofulvin and benzoic acid three drugs under all operating conditions. As known to all, the factors of strongly affecting the morphology and size of crystallized particles via the RESS process can be classified into two categories: thermodynamical parameters and processing parameters. The former mainly includes extraction temperature (TE) [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [24], [25], [28], [29], [32], [33] and pressure (PE) [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [24], [25], [26], [28], [29], [32], [33], [34], [35], [36], pre-extraction temperature (TPrE) [5], [6], [7], [18], [21], [25], [26], [28], [29], [32], [33], [34], [36] and pressure (PPrE) [21], [29], postexpansion temperature (TPoE) [7], [26], [27], [32], [36] and postexpansion pressure (PPoE) [36], and cosolvent content (Cs) [5], [8], [9], [13], [14], [22], [23], [31], [32], influencing the RESS process in terms of solubility and supersaturation, and mass transfer rate. The latter includes nozzle aspect ratio [28] and length (LN) [15], [16], [17], [18], [19], [20], [32], [34], [35], effective nozzle diameter (DN) [6], [8], [10], [11], [13], [14], [15], [16], [17], [18], [19], [20], [24], [25], [26], [27], [28], [29], [33], [36], spray distance (DS) [6], [12], [13], [15], [16], [17], [18], [19], [20], [35], [29], [32], [34] and collision angle [34], affecting the particle size and morphology of the RESS products. The relationship between some RESS process conditions and particle properties has been highlighted in a recent review paper [31] and some recent RESS results are exampled in Table 1. However, the understanding of applying RESS to particle formation and the exploration of its feasibility are still in their infancy and more efforts on it are necessary.

In this work, progesterone (Fig. 1) was used as an interesting drug. It is an extremely important intermediate steroid for the biosynthesis of estrogen and hormone testosterone. It is known that progesterone is essential for correct pregnancy evolution and related to protein transport and the electrolytic balance. Usually, progesterone can be taken orally or used as an injectable drug for achieving biological effects of endogenous hormones or correcting unbalanced hormones, however, its effectiveness is strongly related to the particle size, morphology and other size-dependent properties. As a promising method of comminuting particles, the RESS process was attempted for reproducing progesterone particles. Information for drug solubility is essential for the RESS [37], [38], [39], [40] since the degree of supersaturation determines the rates of nucleation and growth, consequently influences strongly the particle size and morphology. Although the solubility of progesterone in SCCO2 have been reported in the literature [36], [41], [42], there is considerable inconsistency among the experimental data. For these reasons, it seems rewarding to studying the solubility and RESS of progesterone.

The main objectives of this work are as follows: (1) a continuous flow technique coupled with gravimetric analysis was used to measure the solubility of progesterone at 313.15, 323.15 and 338.15   K over a broad pressure range of 120 to 260   bar and a solubility comparison was made with previous solubility data. Then, the experimental solubilities of progesterone in SCCO2 were quantitatively correlated with three density-based correlations and the Peng–Robinson equation of state (PREOS) model. (2) the RESS technique was employed for the particle formation of drug progesterone. The performances of RESS under different conditions in terms of nozzle diameter, extraction pressure and temperature were evaluated by analyzing the particle size and particle size distributions of the precipitated particles. The progesterone particles produced by the RESS process were characterized with numerous analytical methods including SEM, XRD, FTIR, DSC, TGA and in vitro dissolution tests.