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Anderson Albuquerque is pharma tech lab expert at the Global Pharma Tech Laboratory, Merck SA, Rio de Janeiro, Brazil.
Raphael Lopes is pharma tech lab expert, all at the Global Pharma Tech Laboratory, Merck SA, Rio de Janeiro, Brazil.
Renato BP Pinto is head of the Global Pharma Tech Lab at the Global Pharma Tech Laboratory, Merck SA, Rio de Janeiro, Brazil.
Particle morphology of magnesium stearate, added as an anti-caking agent in a high water‑soluble drug substance, has an influence on the dissolution rate of compressed tablets.
Magnesium stearate (MgSt) is the most commonly used lubricant in solid dosage formulations to improve the formulation processability. It may be used as an anti-caking agent when blended in lesser amounts with APIs with high caking potential as a pre-mix for further processing. This approach changes the surface properties of powders by dry coating it with hydrophobic materials to modify the surface energy and reduce particle interaction (1). This process uses shear and compression to produce a thin, continuous film of lubricant on the surface of the host avoiding the caking effect. But, this hydrophobic layer prevents water from penetrating into the tablet, thus restraining the disintegration and dissolution of the tablets (2).
MgSt is a naturally sourced excipient, and the excipient suppliers use a variety of processes to manufacture different MgSt grades for pharmaceutical applications. Not surprisingly, several studies have reported the presence of source-to-source, manufacturer-to-manufacturer, and lot-to-lot variability in the physical, chemical, and functional characteristics of MgSt (3).
It is well-known that MgSt with a larger surface area may cause a slowing-down of the dissolution rate of some APIs (4). However, the influence of MgSt particle morphology and the blending shear rates in the preparation of a pre-mix on the dissolution rate of high soluble API are often neglected. This study highlights the influence of particle morphology of MgSt when blended with high water-soluble drug at low and high shear rate on the dissolution rate of immediate-release tablets.
Materials. Metformin hydrochloride (HCl) was selected as a highly water-soluble drug. MgSt samples were purchased from three different suppliers: Supplier 1 (MgSt S1), Supplier 2 (MgSt S2), and Supplier 3 (MgSt S3). Polyvinylpyrrolidone (PVP) was added as the binder.
MgSt characterization. Surface area (SA) was assessed using the Brunauer-Emmett-Teller (BET) method. Samples were accurately weighed into glass tubing (in the range 1–5 g), and predried at 40 °C for 20 h to remove any surface-attached moisture/solvent. Nitrogen sorption measurements were performed on a ASAP 2420 multistage sorption analyzer (Micromeritics), using highly purified nitrogen as the probe gas at a measurement temperature of –195.85 °C (liquid nitrogen dewar). Sorption measurements were performed in the partial pressure range p/ps 0.03–0.15, with BET multipoint linear regression analysis being performed on seven sorption points in the partial pressure range p/ps 0.05–0.12.
Scanning electron microscopy (SEM) was used to study the agglomeration of the particles. A small amount of powder was prepared on an aluminium sample holder covered by a conductive double-faced adhesive tape. Non-adhered particles were removed from tape by compressed air. To avoid electrostatic charging, the sample was sputtered with platinum (layer thickness: ~10 nm). The prepared sample holder was added into a Leo 1530 scanning electron microscope (ZEISS), and the measurement was performed under high vacuum.
Preparation of pre-mix. About 2 kg of each pre-mix was prepared. 0.5% MgSt was added to Metformin HCl at low shear and high shear mixing rates using a 6-L Laboratory Mixer P 1/6 (Diosna Dierks & Sohne). The low shear mixing rate was run for five minutes with chopper speed at 700 rotations per minute (rpm) and mixer speed at 300 rpm. The high shear mixing rate was run for 10 minutes at chopper speed 2200 rpm and mixer speed at 1000 rpm.
After blending, the pre-mix was allowed to settle for five minutes before unloading the mixer, to reduce material loss due to airborne particles.
Preparation of tablets. All tablets were prepared by the wet granulation method. The pre-mix was granulated with PVP dissolved in water as a binder agent using the 6 L Laboratory Mixer P 1/6 (Diosna Dierks & Sohne). The wet mass was dried using the fluid bed drier Minilab XP (Diosna Dierks & Sohne). Prior to tableting, the dried mass was milled using the conical mill Quadro Comil U3 (Quadro Engineering). The milled granules were formed into tablets using a Korsch XL tablet press (Korsch) equipped with 7 mm compression tooling and 10 mm overfill cam.
The machine setting was kept constant. Tableting speed was set to 10,000 tablets per hour, fill depth was set to obtain a tablet weight of 270 mg, and the main compression was controlled at 15 kN for all experiments.
Dissolution method. The dissolution profile of six tablets of each formulation were tested according to the European Pharmacopoeia (Ph. Eur.) 2.9.3 (5). Each tablet was placed in a vessel filled with 900 mL of purified water at 37 °C ± 0.5 °C. Apparatus 2, with paddles at 50 rotations per minute, was used for stirring. Aliquots were taken at 5, 10, 15, 35, 45, and 60 min and the API dissolved was quantified by ultraviolet-visible spectrophotometry.
To evaluate the effect of shear rate in the preparation of the pre-mix on the dissolution of immediate-release tablets, the Metformin HCl was blended in the mixing equipment with MgSt from different suppliers at high shear and low shear rates. The formulations were then compressed into tablets, and the dissolution profile of six tablets was tested.
Impeller, chopper speed, and mixing time were varied according to Table I. All other machine settings were kept constant during the experiment.
Table II depicts the SA measurements obtained by BET determination of MgSt samples. These samples were added in Metformin HCl and blended at high and low shear rate to prepare the free-flowing pre-mix. The pre-mix was used to prepare the immediateârelease tablets. The dissolution profiles of the tablets were tested.
Figure 1 depicts the images obtained by scanning electron microscopy (SEM) of MgSt samples, illustrating the difference in particle morphology. Figure 2 depicts the Metformin hydrochloride (HCl) dissolution profile of the tablets prepared with the pre-mix, with which the magnesium stearates (MgSt S1, MgSt S2, or MgSt S3) were blended. Figures 3–5 depict the Metformin HCl dissolution profile comparison of the tablets prepared with the pre-mix blended at high and low shear rates for each of the three MgSt types.
The SA plays a key role in the effect of the MgSt on the dissolution rate of some APIs from tablets. This effect is related to the ability of MgSt to cover the particles of the excipients and API during the tablet’s manufacturing process. As MgSt is not water soluble, an excessive coating may lead to a slower dissolution rate of the active ingredient from the tablet.
The samples of MgSt obtained from various vendors tested have different particle properties, such as specific surface area and particle morphology, as shown in Table II and Figure 1. MgSt S1 sample has the highest surface area of all, followed by the MgSt S3 sample. MgSt S2 sample has the lowest (see Table II).
The SEM pictures (Figure 1) depict differences in particle morphology. MgSt S1 and MgSt S3 samples are agglomerated, flake-like particles, while MgSt S2 particles are more consistent and smoother.
Generally, it is expected that the slow-down of Metformin dissolution rate, due to the MgSt effect, increases on increasing the surface area of MgSt. The increase of surface area can provide more API coverage with the excipient, which is hydrophobic.
Metformin tablets prepared with the pre-mix with MgSt S2, which has the lowest surface area of all, had a faster dissolution rate than tablets prepared with the pre-mix with MgSt S1 and Mg St S3. Despite MgSt S3 sample having a lower surface area value than MgSt S1 sample, Metformin tablets prepared with the pre-mix with MgSt S3 and MgSt S1 had unexpectedly similar dissolution rates, Figure 2.
The dissolution rate of the Metformin tablets was found to be slower when MgSt S3 and MgSt S1 were used in the preparation of the pre-mix blended at higher shear rates, see Figures 3 and 5. But no shift was found when the MgSt S2 was used to prepare the pre-mix at both shear rates, see Figure 4.
It is suggested, in specific literature, that particle morphology of some MgSt is often pictured as a deck of cards depending on the precipitation process during its preparation (6). During the blending process with active ingredients, carriers, or fillers, the ‘plates’ of MgSt dismantle from the decks, piece-by-piece, to coat other particles, depending on the particle morphology.
MgSt S2 particles are less susceptible to deagglomeration by shear rates during blending due to the more consistent and smoother morphology. MgSt S1 and MgSt S3 agglomerated flake particles, however, are more susceptible to being dismantled, increasing their coverage potential. The coverage by such a hydrophobic layer prevents water from penetrating into the tablet, leading to a slower dissolution rate when prepared with the pre-mix with MgSt S1 and MgSt S3.
The specific surface area is not the only driver for the potential coverage of MgSt particles over API and excipients, but particle morphology also plays a key role, mainly when MgSt is blended at higher shear rates with an API for further processing as a pre-mix. Agglomerated flake-like particles are more susceptible to being deagglomerated and have higher coverage potential than the more consistent and smoother particles, despite surface area. The increased coverage potential prevents water from penetrating into the tablets prepared with such a pre-mix, leading to a slower dissolution rate.
1. R. Pfeffer, et al., Powder Technology 158 (1–3) 21–23 (2005).
2. G.K. Bolhuis, A.J. Smallenbroek, and C.F. Lerk, J. Pharm. Sci. 70 (12) 1328–1330 (1981).
3. J. Barra, and R. Somma, Drug Dev. Ind. Pharm. 22 (11) 1105–1120 (1996).
4. T.A. Miller and P. York, Int. J. Pharm. 23 (1) 55–67 (1985).
5. EDQM, Ph. Eur., General Chapter 2.9.3, Dissolution Test for Solid Dosage Forms (EDQM, Strasbourg, France, 2014).
6. Peter Greven, “Ligamed Brochure,” peter-greven.de.
Vol. 43, No. 5
When referring to this article, please cite it as Renato BP Pinto, Anderson Albuquerque, and Raphael Lopes, “Role of Particle Morphology on Tablet Dissolution Rates,” Pharmaceutical Technology 43 (5) 2019.