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The authors examine the use of various grades of direct-compression mannitol in direct-compression tableting process to evaluate the content uniformity of micronized APIs and excipients in a solid-dosage formulation.
There are several reasons to micronize APIs in a solid-dosage formulation. Many new drug molecules are poorly soluble, and one means to enhance solubility is to enlarge surface area by micronizing the API. Obtaining a homogenous mixture of the micronized API and excipients in a solid dose and maintaining product stability, however, can be challenging. Additionally, micronized APIs are used in the formulation of highly potent drugs that require low dosage. In this case, content uniformity is crucial and difficult to achieve when seeking to evenly distribute content of less than 1% API in a solid formulation.
The pure physical mixture based on statistical distribution often has no stability of homogeneity. For this reason, many formulators switch to more expensive wet- or dry-granulation processes instead of direct compression (DC) or sachet formulations. A mixture has the best chance for stability if the particles of the API and excipients are of the same size range (1). For handling reasons, the mixture of excipients and API should be in a granulate form rather than in powdered form.
The purpose of this study was to evaluate whether such APIs could create stable mixtures with larger excipient particles and support a DC-tableting process with good content uniformity. An earlier study demonstrated the stability of so-called "ordered mixtures" with spray-dried sorbitol and much smaller API particles (2, 3). Hersey first introduced the concept of ordered mixtures to explain the behavior of interacting particles in a powder mixture (4).
These examples from the literature dealt with spray-dried sorbitol, which at the time, was a rare example of a DC excipient. Today, mannitol is used as a DC excipient due to its inertness, its low hygroscopicity and its fast-release qualities. The study in this article focuses on different DC-grades of mannitol available on the market.
Materials and methods
Two types of spray-dried DC-mannitol were used, respectively named in this study as DC-Mannitol A and DC-Mannitol M, and one type of granulated mannitol, DC-Mannitol B (see Table I). The model APIs used were ascorbic acid as an example of a hydrophilic compound and riboflavin as a hydrophobic compound. Both APIs were micronized on a pin mill before using them for this case study (see Table I).
Table I: Physical characteristics of applied excipients and APIs*.
API–mannitol mixtures (batch size 300 g) were prepared using a shaker-mixer (Turbula T2C, Willy A. Bachofen AG Maschinenfabrik). To evaluate the quality of mixing, the homogeneity was measured by taking six samples from the mixtures and applying a sample divider (Retsch Type RT 6.5, Retsch AG) after a specified period of mixing time (2, 5, 10, 20 and 30 min). The procedure was repeated three times.
The API content in each sample was analyzed (n = 18). For ascorbic acid, the content was determined through a volumetric analysis by titration with an iodine solution (TitriPUR, Merck KGaA), which provided an accuracy of measurement with a relative standard deviation (RSD) of 0.12%. The riboflavin content was determined spectrophotometrically at 444 nm according to the European Pharmacopoeia (5). The RSD of the API concentration was examined as a function of mixing time (see Figures 1 and 2).
Figure 1: The relative standard deviation (RSD) of the API content in relation to the mixing time of the APIâdirect compresson (DC)-Mannitol M samples (drug load 1% w/w). (FIGURES ARE COURTESY OF THE AUTHOR)
To challenge the mixture stability and to show the strength of adsorption of low-dose formulations, API–DC-mannitol mixtures with a drug content of 1% and 3% were applied to an Alpine air jet-sieve (A 200 LS, Hosokawa Alpine) and analyzed for their drug content after 15 min of airflow. The applied mesh size was 40 μm, and the vacuum pressure was 2000 mPa. Separately, the capability of a stable, direct-compression process was further investigated using a water-sensitive low-dose drug in a pharmaceutical formulation. The results of this investigation are later discussed under the "Results of field testing in a R&D case study" portion of this article.
Figure 2: Relative standard deviation (RSD) of the API concentration (1% ascorbic acid/riboflavin, micronized) in samples containing a model API and different direct-compression (DC)-mannitols as excipients.
The reduction of the RSD of the measured API concentrations shows how the mixture approaches homogeneity with rising mixing times (see Figure 1). A time of 30 min was chosen as sufficient to view the mixture of DC-mannitol with micronized ascorbic acid as homogeneous (RSD = 0.67%). The mixing behavior of a blend is dependent on the API and the excipient, as well as on mixer type, scale, and the degree of filling of the mixer. As the latter parameters were constant for all assessed blends, differences in homogeneity must be due to either the API or the excipient. In this case, the micronized hydrophobic particles of riboflavin tend to re-agglomerate during mixing. This re-agglomeration is why at first the homogeneity decreases before the mixture reaches a steady state (see Figure 1).
The resulting mixing time of 30 min seems to be rather high. It has to be taken into account that this small laboratory-scale mixing unit is certainly not optimized. More importantly, however, the micronized API granules have a tendency of agglomeration to each other due to their high surface energy. This binding force has to be broken up and replaced by an alternative binding force—adsorption and van der Vaals interaction–with the carrier surface. This is a dynamic equilibrium process and takes more time than just a statistical distribution of different particles in space.
The comparison of different DC-mannitols at optimum mixing time reveals differences in the homogeneity of such a mixture with micronized ascorbic acid and riboflavin (see Figure 2). Clearly, for a hydrophilic API, the achievable homogeneity is greater than for a hydrophobic API. In this case, the different attraction forces of the hydrophobic API to a hydrophilic carrier cause more API particles to re-agglomerate rather than bind to the carrier surface. This is not a surprising observation because this relationship would be true for all excipients. There are, however, differences in the achievable blend uniformity among the compared carriers. The best homogeneity for both API cases was found for the excipient with the highest surface area, DC-Mannitol M (see Table I). This observation gives a hint for a correlation of BET surface area and/or pore volume to the achievable homogeneity. There also are significant differences between spray-dried and granulated DC-mannitol even having similar BET-surfaces (see Figure 3). The quality of the surface structure, not only the quantitative size of the surface area, seems to be relevant.
Figure 3: Comparison of the surface area and pore volumes of different excipients available for direct compression. DC is direct compression. Parkteck M 200 is a proprietary product of DC-grade mannitol (Merck KGaA). Sp is specific.
To prove an adsorption of the API to the excipient surface with a certain force, the remaining concentration of ascorbic acid and riboflavin was measured after 15 min on an air-jet sieve. By this procedure, a separation of fine API particles from the carrier can be expected if they were not strongly adsorbed. A recovery of 100% would mean a perfectly strong adsorption of the API to the carrier while a recovery of 0% shows no absorption to the carrier.
A much stronger adsorption was found for the spray-dried DC-mannitols in comparison to the granulated quality (see Figure 4). For low API concentrations of a hydrophilic drug, both spray-dried mannitols show similar results. Using higher API loads, it was demonstrated that the higher surface area of DC-Mannitol M shows advantages of a higher binding capacity. This effect was confirmed with a hydrophobic API, riboflavin. This finding may again result from the different surface structure of the investigated excipients. The lower recovery of hydrophobic API again confirms a weaker force of surface adsorption by this class of API.
Figure 4: Comparison of the API concentration measured after 15 min in an air-jet sieve using either granulated direct-compression (DC)-Mannitol B, spray-dried DC-Mannitol A, or DC-mannitol M as excipients for the model drugs of ascorbic acid or riboflavin.
To visualize the API distribution on the excipients' surface, a scanning electron microscope (SEM) was employed. Figure 5 shows the SEM image of a mixture of ascorbic acid and DC-mannitol M. The micronized API particles are readily identifiable due to the different crystal structures of API and carrier (colorization performed manually). The API crystals were found within the pore structure of the much larger excipient particles. Figure 6 shows the SEM image of spray-dried DC-Mannitol A and ascorbic acid. In this case, less areas are present that are suitable for the absorption of the API. The overall surface is less structured. A similar distribution on the excipients' surface was determined for the hydrophobic model drug riboflavin (see Figure 7).
Figure 5: Scanning electron microscope (SEM) image showing a mixture of direct-compression (DC)-mannitol M 200 and micronized ascorbic acid (drug load 1% w/w).
The importance of the surface area and the pore volume of an excipient for the homogeneity of the mixture was demonstrated. In the next step, the surface area and porosity of various excipients available for direct compression were analyzed using the BET method (nitrogen adsorption). As the API is adsorbed to a porous surface, the observed differences of the excipients may give rise to a different behavior in the adsorption of the micronized APIs (see Figure 3).
Figure 6: Scanning electron microscope (SEM) image showing a mixture of spray-dried direct compression (DC)-Mannitol A and micronized ascorbic acid (drug load 1% w/w).
This study showed that stable mixtures of much smaller micronized API particles with DC-excipients can be achieved. The next question examined was whether this approach was suitable for the DC process for an actual formulation.
Figure 7: Mixture of direct-compression (DC)- mannitol M 200 with micronized riboflavin (drug load 1% w/w). Light microscope with 40 x magnification. The yellow particles of the API are clearly visible in the porosity of the carrier surface.
Results of field testing in a R&D case study
The question whether low-dose pharmaceutical formulations with micronized APIs are suitable for a DC process was challenged using a water-sensitive R&D API at only 0.4% in the final dosage form (0.5 mg API in a 120-mg tablet). Wet granulation could not be applied because of the water-sensitivity of the API. The micronized API (Dv50 10 μm), therefore, was premixed for 30 min using a shaker-mixer (Turbula T2C) with 15% of the total amount of DC-grade mannitol DC-Mannitol M (Dv50 200 μm) and mixed with the rest of the formulation using a Turbula T20P (Bachofen AG) (see Figure 8). A test run of 2 h on a rotary press (Korsch Pharmapress PH230, Korsch AG) was performed at two different rotation speeds (40,000 and 80,000 tablets/h). The tablets were assessed for their weight, hardness, and disintegration time.
Figure 8: Composition of the investigated pharmaceutical formulation used for the R&D case study.
This result was surprisingly good as constant values were detected for tablet weight (RSD 0.6–0.9%), tablet hardness (RSD 4.1%), and disintegration time (see Table II). Content uniformity was measured to be ± 1.8 %.
Table II: Comparison of tablets manufactured at different speeds of the rotary press.
Although the concept of ordered mixtures has been extensively studied and reported, little was known about the mechanisms and reasons behind ordered mixtures (6–9). The results clearly show that the effect of ordered mixtures can be found with DC-mannitols as a function of surface area and structure. To a greater extent, this functionality can be found for spray-dried qualities with a porous surface structure. A large surface area is helpful for good binding capacity. Stable mixtures are not only achieved with components of similar particle sizes as the literature suggests. It is also possible to achieve a stable mixture of micronized API particles (< 15 μm) with a DC-mannitol with a mean particle size of 200 μm. The stability is caused by an adsorptive binding force strong enough to withstand the mechanical separation forces. This effect was successfully demonstrated for hydrophilic and hydrophobic APIs. This result confirms the feasibility of DC for low-dose applications with acceptable content uniformity as the example showed. It also helps to show that micronized APIs at higher concentrations can be applied in solid formulations to enhance their solubility. This approach can be applied for DC, sachet formulations, or in roller compaction.
H. Leonhard Ohrem* is a technical manager, firstname.lastname@example.org, Roberto Ognibene is head of the formulation laboratory, and Thorsten Wedel is a pharmaceutical engineer, all with Merck KGaA, Darmstadt, Germany 64271.
*To whom all correspondence should be addressed.
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