Jerome Hansen and Peter Kleinebudde
The direct compression of powder blends into tablets can only be realized if the material has sufficient flow properties to ensure a homogeneous filling of the die during tableting. Poor flowability of an API, such as metformin hydrochloride (MF), can lead to the need for an intermediary granulation step. Particle engineering can be used to change e.g. the flowability and micromeritic properties of an API or excipient without changing its chemical, pharmacological or crystalline properties. Quasi-emulsion solvent-diffusion (QESD) crystallizations offer such a platform to produce hollow, spherical agglomerates of an API or excipient which can be directly compressed into tablets. Hereby, a material is crystallized and agglomerated within transient emulsion droplets to improve various product attributes, such as tabletability [1], flowability [2], tendency towards punch sticking [3] and the dissolution profile [4].
Figure 1. SEM images of MF crystalized using an antisolvent (left) and a stabilized QESD crystallization (right)
Metformin hydrochloride is a drug used in the treatment of non-insulin-dependent diabetes mellitus and is given orally in the form of tablets with a high drug load (500-1000 mg) [5]. Due to its poor flowability (Hauser ratio: 1.71 ± 0.03, angle of repose: 58° ± 0.4) a wet or dry granulation step is usually required to improve the flowability of the bulk material. Changing the morphology of the MF particles to improve their flowability would allow for a direct compression of a powder blend, reducing production time and costs. Quasi-emulsion solvent-diffusion crystallizations offer such a platform, to create hollow, spherical agglomeration in a single production step. Using a crystallization for particle engineering is useful, as it is often already part of the final purification step of an API or excipient.
In the simplest term, a QESD crystallization is a stabilized antisolvent crystallization. An API solution is dispersed in a miscible antisolvent. Stabilizers are often added to allow for the formation of a transient emulsion and to reduce the rate of counter diffusion of solvent and antisolvent to and from the droplets. During crystallization, the antisolvent fraction within each droplet increases due to diffusion which leads to the formation of a supersaturated solution. Nucleation and crystal growth occurs near the interface of the droplets, as the level of supersaturation is highest there due to the proximity to the outer antisolvent phase [6]. Similar to spray drying, further dissolved material solidifies to the initial crust, creating spherical, hollow agglomerates.
MF can be spherically crystallized using the QESD method using a simple lab-scale batch crystallizer [2]. For this, an aqueous MF solution (41.9 %, w/w, 57 °C) is dispersed in acetone (20 °C) under constant stirring. Hypromellose (Pharmacoat ® 603, Shin-Etsu, 1.42 %, w/w) is added to the aqueous solution as a QESD stabilizer. It stabilizes the transient emulsion by increasing the viscosity of the aqueous phase and reducing the interfacial tension. Furthermore, the interaction between the polymer and API at the interface leads to the formation of a smooth surface (Fig. 1) which allows for a good flowability of the material [7]. An antisolvent crystallization of MF in acetone without the use of a stabilizer yield irregular particles (Fig. 1) with poor flowability.
After filtration, washing and drying, a freely flowing powder (Hausner ratio: 1.17 ± 0.02, angle of repose: 31° ± 0.8) consisting of spherical, porous agglomerates was obtained. The particle size of the agglomerates can be influenced by changing the droplet size of the emulsion, e.g. by changing the stirring speed [2, 6] and therefore changing the input of mechanical energy into the system. Furthermore, the diffusion rates of solvent can be changed by e.g. changing the antisolvent temperature or solvent fraction of the mother liquor. The latter is of great importance, as the increasing solvent fraction in the mother liquor during the course of API solution addition leads to the formation of smaller agglomerates during the batch crystallization process.
The good flowability of QESD MF allowed for the direct compression of its powder blend into tablets containing > 90 % MF with sufficient strength and mass uniformity [1]. For the tableting trial a compaction simulator was used (Styl’One Evolution, Medelpharm). Hyprolose (5 %, HPC SSL SFP, Nippon Soda) was added as a binder and 0.5 % magnesium stearate for internal lubrication. The tabletability plot (Fig. 2) showed a higher tablet strength of the QESD MF tablets compared to those produced with the unprocessed reference material. The hollow spheres of QESD MF can break during compression so that new bonding areas can be formed. Even though deaeration issues were initially observed due to the low bulk density of the porous material (~ 0.25 g/mL) which led to tablet capping, this issue could be overcome by the use precompression cycles. Herewith tablets could be produced at simulated speeds of up to 150,000 tablets/h on a Korsch XL400 rotary tablet press (Fig. 2).
Figure 2. Tensile strength of tablets produced with A. QESD MF compared to the reference material (mean ± s, n = 6) and B. at different simulated turret speed of a Korsch XL400 (precompression: 50 MPa, main compression: 185 MPa, mean ± s, n = 10)
Under storage, MF tends to agglomerate into solid blocks so that fresh milling and quick processing of the material is normally required. Crystallizing MF using the QESD method not only lead to a superior tabletability compared to the reference material but also improved its storage agglomeration tendecy. The QESD material did not show this tendency [2] due to the reduction in the amount of contant points between the particles through their size enlragement and the likely presence of HPMC on the crystal surface. Storage for 1 year was possible under climate conditions (21 °C, 45 % RH).
Using a QESD crystallization as a means of particle engineering allowed for the direct compression of MF. A simple crystallization formulation was developed which only required the addition of hypromellose as a stabilizer to obtain spherical, hollow agglomerates. The improved morphology of the particles resulted in a powder with good flowability, improved tabletability and reduced tendencies towards storage agglomeration compared to the reference material.
References:
[1] J. Hansen, P. Kleinebudde, Enabling the direct compression of metformin hydrochloride through QESD crystallization, International Journal of Pharmaceutics, 605 (2021) 120796.
[2] J. Hansen, P. Kleinebudde, Improving flowability and reducing storage agglomeration of metformin hydrochloride through QESD crystallization, European Journal of Pharmaceutics and Biopharmaceutics, 159 (2021) 170-176.
[3] H. Chen, S. Paul, H. Xu, K. Wang, M.K. Mahanthappa, C.C. Sun, Reduction of Punch-Sticking Propensity of Celecoxib by Spherical Crystallization via Polymer Assisted Quasi-Emulsion Solvent Diffusion, Mol Pharm, 17 (2020) 1387-1396.
[4] A. Sano, T. Kuriki, Y. Kawashima, H. Takeuchi, T. Hino, T. Niwa, Particle design of tolbutamide by the spherical crystallization technique. V. Improvement of dissolution and bioavailability of direct compressed tablets prepared using tolbutamide agglomerated crystals, Chemical and pharmaceutical bulletin, 40 (1992) 3030-3035.
[5] C.J. Bailey, R.C. Turner, Metformin, New England Journal of Medicine, 334 (1996) 574-579.
[6] F. Espitalier, B. Biscans, C. Laguerie, Particle design Part B: batch quasi-emulsion process and mechanism of grain formation of ketoprofen, Chemical Engineering Journal, 68 (1997) 103-114.
[7] J. Hansen, P. Kleinebudde, Towards a better understanding of the role of stabilizers in QESD crystallizations, Pharmaceutical Research, (2022) 1-14.
