Pharmaceutical powder processing poses many challenges.  One of the most difficult is achieving acceptable dose uniformity, to protect patients by helping to ensure that the amount of drug substance in each individual dosage form remains the same. 

Different manufacturing methods can result in different content uniformity issues. In this article, we compare results we found using geometric dilution, wet granulation and a dry blend process to manufacture a low-dose, immediate-release solid dosage form.
We used content uniformity, as defined by USP , to determine dose uniformity.  We also considered the adequacy of mixing to ensure uniformity and homogeneity, as required by the current good manufacturing practices (cGMPs), specifically 21 CFR 211.11 O (a)(3)).

Particle properties of the API and diluents play a major role in achieving homogeneity. It is crucial to understand such parameters as particle size, particle shape, density, and cohesiveness before selecting a process for mixing¹. Additionally, the particle size difference between the API and diluent can affect segregation during processing². Dose uniformity also depends on the formulation and the powder blending technique selected.  Events such as inadequate weight control and insufficient blending can cause failure of content uniformity³.

Following is a rough summary of manufacturing processes typically used for low-dose solid dosage forms.

Comparing Methods: Pros and Cons
Wet granulation is a process where API is dissolved in the spray solution. The spray solution is sprayed uniformly onto a powder bed to give wet granules that are then dried in a fluid bed dryer or an oven. Wet granulation can be a low shear, high shear or fluid bed process depending on formulation and equipment availability. We chose to study high shear wet granulation, since flow, uniform distribution of drug and good compactability can all be built into the process without relying heavily on the API particle properties.⁴ Additionally, it can bring the disintegrant and other excipients into very close contact with the API, which can help with disintegration and dissolution.  For a low-dose formulation, wet granulation helps to fix the API particle within the granulation and thus prevents segregation during processing.  Disadvantages of wet granulation include the fact that it can introduce water and heat into the formulation, which can cause chemical instabilities.  Additionally scaling up with a wet granulation process can be challenging⁴.

Geometric dilution is used when blending two or more ingredients of unequal quantities.  The API is blended with excipients in equal proportions until all excipients have been thoroughly mixed. This method, on a small scale, typically includes triturating the API with an equal quantity of diluent, using a mortar and pestle to achieve an intimate mix. This powder blend is then mixed again with an equal portion of diluents.  This process continues until all of the diluent has been mixed. 

This method offers the added advantage of not subjecting the API to liquid contact. However, it can be very time consuming and can require a significant investment in equipment for blending. Additionally, every time the API blend is transferred from one mixing vessel to the next, there is a possibility that a fraction of the API is left behind in the previous vessel resulting in lower API content in the final vessel.

Developing a Dry Blend Method
We developed a dry blend method, as summarized and contrasted with more traditional methods in Figure 1.  A key focus was particle size, since it is a major determinant of dose uniformity results. Several theories are available to predict dose uniformity based on particle size.  Yalkowsky and Bolton derived an equation5 for measuring the drug content variations with the following assumptions:

• homogenous mixing
• particle size distribution described by log-normal function

This was a good method when it was developed in 1990, but since then the USP criteria for content uniformity have changed. Rohrs and Amidon modified the Yalkowsky-Bolton method to include current USP criteria for tablets6. They provide a method of estimating the required particles size to achieve good content uniformity based on dose, mean particle size distribution, and particle distribution width using a modified version of the Yalkowsky-Bolton method.  They generated a diameter-to-dose relationship using the modified Yalkowsky-Bolton method to show the maximum acceptable particle size (d50) and distribution width (Óg) needed in order to pass Stage I USP criteria for tablets for a given dosage strength. 

Particle size of API used for the batches discussed in this paper was reduced using a wet milling process.  Particle size was analyzed using Saturn DigiSizer II 5205.  Particle size results are shown in Table 1. According to the model presented by Rohrs and Amidon, the particle size distribution of the API is sufficient to pass content uniformity criteria for 0.2-mg tablet dose⁸.

Selecting the right carrier excipient was also crucial.  Augsberger has said that “ordered mixing,” in which fine API particules are adsorbed onto larger carrier particles, can be used for low-dose formulations⁹. If the carrier particles are uniform in size, ideal mixing can be achieved.  Additionally, this adsorption helps to minimize segregation during processing.

Silicified microcrystalline cellulose (Prosolv SMCC90 from JRS Pharma)¹⁰ was selected as the carrier particle for this process.  Prosolv 90 not only has good flow, but also has a creviced surface for good API adsorption. Sodium starch glycolate and magnesium stearate were selected as the tablet disintegrant and lubricant to give the candidate formulation (Table 2). 

The next step was to develop a simple process for tablet manufacture. As mentioned previously, wet granulation and geometric dilution were considered.  However, the goal was a simpler process.  A high energy blending process was developed with the first blending step within a high shear mixer.   The next steps were milling the blend for added mixing without particle size reduction followed by lubrication in a bin blender.  The equipment used in this process is shown in Table 3.

RESULTS AND DISCUSSION
A side-by-side comparison of the three processes mentioned in this paper is shown in Figure 1. The wet granulation and geometric dilution processes both contain at least five different steps for blending.  In comparison, the dry blend method only has two blending steps.  From an operations standpoint, set-up and cleaning of three additional pieces of equipment can take considerable time and manpower. Overall, the process for dry blending utilizes only four major pieces of equipment, which is about half of that used for either of the other two processes (seven for Wet Granulation, seven for Geometric Dilution).

It can be argued that, although wet granulation and geometric dilution processes include more unit steps, they are still robust processes used in the industry.  However, with the increasing push for Quality by Design (QbD) to be implemented into the product development process, the number of process steps becomes critical.  For a process such as wet granulation the number of critical process parameters (CPP) to be studied can be well over twenty.  Table 4 shows the CPP involved for each of the three processes.  Since the dry blending process uses less equipment overall, there are fewer CPPs to be considered during development.

Analytical results of batches manufactured at the development scale using the dry blend method were compared to that of batches manufactured using wet granulation and geometric dilution in Figures 1 – 3.  The %RSD’s for batches made using the dry blend method were below 4% for all six batches.  The %RSD’s for the wet and geometric dilution batches were also acceptable.  Content uniformity results overall were comparable to a wet granulation or geometric dilution process.

Two 25-kg batches were prepared using the dry blend process. Tablet samples were pulled at various points during compression and tested for content uniformity.  Segregation was not observed during the compression process.  Figures 5 and 6 show that content uniformity results from beginning to end of compression were acceptable.

Several clinical batches, also at the 25-kg scale, were manufactured following successful scale-up of the development batches.  Clinical batches manufactured using the dry blend process have all exhibited excellent content uniformity results (Figure 7).  RSD values for all batches were below 2%. 

A dry blending process is very streamlined and uses only a few pieces of equipment.  However, as is true with any process, steps must be taken to optimize results. For example, before adding API into the high shear mixer, the mixer bowl must first be coated with diluent. Also, the API should be “sandwiched” between two layers of the diluent inside of the high shear mixer bowl.  These measures prevent API particles from sticking to the surfaces of the mixer bowl.  Once the API has been mixed inside the high shear mixer, the blend is homogenous.  Therefore, there is no fear of a high concentration of API being left behind on any one piece of equipment.

Results suggest that dry blend method might be able to achieve content uniformity results comparable to those achieved with wet granulation and geometric dilution, but with fewer processing steps and equipment requirements.  The technique can also facilitate the use of QbD approaches for drug development. 

References

1. Deveswaran R. et al. 2009. Concepts and Techniques of Pharmaceutical Powder Mixing Process: A Current Update. Research J. Pharm and Tech. 245 – 249.
2. Guidance for Industry: Powder Blends and Dosage Units – In-Process Blend and Dosage Unit Inspection for Content Uniformity, Jan 2004.
3. Deveswaran, op cit
4. Introduction to tableting by wet granulation. DFE Pharma
5. Yalkowsky, Samuel H. and Bolton, Sanford. 1990. Particle Size and Content Uniformity. Pharmaceutical Research 7: 962-966.
6. Rohrs, Brian R. et al. 2006. Particle Size Limits to Meet USP Content Uniformity Criteria for Tablets and Capsules. Journal of Pharmaceutical Sciences 95: 1049-1059.
7. Introduction to tableting by wet granulation. DFE Pharma
8. Guidance for Industry: Powder Blends and Dosage Units – In-Process Blend and Dosage Unit Inspection for Content Uniformity, Jan 2004.
9. Augsberger, Larry L., A Technical Discussion of Blending, 1999.
10. “Prosolv SMCC Basic Description.” Prosolv SMCC. Web. 10Feb.2014.
11. Yalkowsky, Samuel H. and Bolton, Sanford. 1990. Particle Size and Content Uniformity. Pharmaceutical Research 7: 962-966.

Additional Resource
Chowhan, Z. T., “Segregation of Particulate Solids, Part I”, Pharmaceutical Technology, May 1995.

ACKNOWLEDGEMENTS
Thanks to Dr. Edward C. Scholtz and Dr. David Hedden for their technical input, and to Mathew Ferrell and Dr. Yanyin Yang for generating the analytical data.

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Julie Kuriakose is a Project Coordinator for UPM Pharmaceuticals, Inc. She holds a B. Sc. in Chemical Engineering and has been in pharmaceutical formulation development for eight years.