Excipients are a very diverse set of materials and simple descriptions are simply not detailed enough to capture their complexity. For example, "lactose" can exist both as anhydrous and hydrate crystals, it can vary considerably in its compaction properties depending on how it is processed and vary in its anomeric content.
In order to specify the required characteristic of the excipients used in any given formulation, excipient descriptions need to include much more information than the chemical composition or common name that is used in standard reference texts. It is not unreasonable to suggest that some type of systematic classification or naming system--"taxonomy"--is required to specify exactly what excipients are to be used in any given formulation. Case studies will be presented to better recognize basic taxonomy approaches with an eye toward the excipient landscape and understand the gaps in current excipient classification and nomenclature.
However, there can be also possibility of their other varied thoughtful of usage. It happens due the thinking and intention of the Product Development Formulator about why, where and how to use a particular excipient and its specific grade for a desired function in his formulation approach. This may not be understandable to a CMC reviewer of regulatory agency who has no former Pharmaceutics background or experience of product formulation specifically for ANDAs of PIV category, where the challenge is designing of a formulation that would out loop the patent of the RLD, i.e., not infrangible.
Below are a few examples of such cases of using excipients of certain grade specifically in Product Development of ANDA drug products under PIV paradigm from Pharmaceutics perspective:
Case 1: Use of two grades of an Excipient as drug career and flow property enhancer for CU & BU respectively.
In a formulation of solid dosage form for a tablet having very low drug load, less than 1.0% a small quantity of Anhydrous Lactose due was used as a career due to its rugged surface to hold the drug substance. It was done by making an initial Premix concentrate for the drug substance. The drug substance was sandwiched between two layers of lactose anhydrous. Thus, the small quantities of the API became attached with the rugged surface of the anhydrous lactose, which would not easily separate. This helped ultimate BU and CU quality of the final blend and drug product respectively.
However, for a dry blend direct compression final blend there was a need for the blended materials' good flow property. Hence, for the rest of the blend material, anhydrous lactose could not be used formits poor flow property. Therefore, in the next step Lactose Monohydrate Fast Flo with microcrystalline cellulose grade Avicel PH102 were used by ordered mixing steps. Thus, in this particular formulation approach two different grade of lactose were used for providing drug career and flow enhancement properties respectively.
Case 2: To improve the segregation characteristics of an API with high bulk density to meet BU in a dry blend and ultimate tablet CU by a D.C method of manufacture. The problem inheriting with the drug substance was due to its high bulk density resulting in segregation.
The active pharmaceutical ingredient Galantamine HBr has a relatively high bulk density (~ 0.6g/ml). Hence, segregation characteristics resulting in blend and ultimately tablets content uniformity issue. Therefore, it is difficult to formulate a direct compression formula for the drug product.
A study was conducted to evaluate the effect of microcrystalline cellulose with a particle size of 50 micron and density of 0.42g/mL on product performance characteristics in relation to content uniformity. Lactose Monohydrate Modified, NF (Fast Flo) was considered as a constant item to be used as a filler to keep the final weights of the tablet same.
For the formulation consideration from the pharmaceutics perspective for the specific API Galantamine HBr with bulk density of 0.4 to 0.6 g/cc originated from plant source daffodil flower the following factors were of very critical:
- Microcrystalline Cellulose and/or modified microcrystalline cellulose with or without silicone dioxide with a bulk density of 0.4 to 0.5 g/mL
- Lactose monohydrate modified, NF (Fast Flo # 316) with a bulk density of approximately 0.7g/mL
- Selectively mixing of the API with a right proportion of microcrystalline cellulose, (Avicel PH 301) with colloidal silicon silicone dioxide. Selectively milling of the pre-mix through a mill (Fitz Mill having rotating knives and/or blades with indicated milling configuration (Hammer Forward and screen opening mesh sizes).
From the results of data with a Blend Uniformity, Mean Assay, 99.0% label claim and with a RSD of 1.2% became evident that the inclusion of the grade Avicel PH 301 of microcrystalline cellulose bulk density 0.4 to 0.5 g/mL along with lactose monohydrate modified, NF (Fast Flo # 316) with a bulk density of approximately 0.7g/mL in the formula provided blend uniformity and final tablet’s content uniformity.
Therefore, microcrystalline cellulose, (Avicel PH 301) having bulk density 0.4 to 0.5 g/mL was found as an essential ingredient for a direct compression formula for the drug product.
Related: Pharmaceutical Excipients in QbD
Case 3: Need of change in the grade of an excipient (hydrophilic polymer) from high molecular weight grade to a low molecular weight grade from Drug Product Stability perspective happened due to a chemical reaction potential in formulation process.
Background: The Exhibit Batch tablets of Bupropion HCl SR 150mg at one month accelerated stability had a very high drug release within one hour (dose dumping) as opposed to 12 hours sustained release property.
This is about the excipient used for achieving sustained release function undergone chemical reaction with the stabilizing agent used for the drug product leading to product quality failure from the desired dissolution behavior. The generic version of Bupropion HCl SR 150 mg, i.e. sustained (12 hours) release tablet was made by matrix design using the excipient hydrophilic polymer Hydroxypropyl Cellulose; Klucel® HXF Pharm grade.
There was the pre knowledge that Bupropion HCl drug product needs a micro-environmental pH ≤ 5.0 for its stability. Thus, the matrix formulation may need the use of a stabilizer.
Technology
- Sustained-release hydrophilic matrix dosage form by swelling and erosion (same as RLD)
Challenges Faced
- Finding a suitable polymer for hydrophilic matrix dosage form
- Selecting an acidifying agent (buffer) that will keep product micro-environmental pH ≤ 5.0
- Use of dilute hydrochloric acid as a granulating fluid and its potential impact on corrosion of stainless steel equipment.
Formulation Approaches
Like RLD tablets generic SR tablets were made by matrix technology. The excipient hydrophilic polymer, a hydroxypropylcellulose Klucel® HXF Pharm grade was used as the polymer for the primary approach for a matrix tablet.
Three exhibit batches (one of each, 100mg, 150mg and 200mg) of Bupropion SR Tablets were manufactured. These initial tablets were analyzed for drug release from the dosage form. The dissolution profile was satisfactory with a desired profile where the drug release is controlled to release up to 10-12 hours.
These tablets were in place for stability under the following conditions: Stress at 50C/75%, accelerated condition of 40/75 and Room condition at 25C/60. Upon stability, the stress and accelerated samples were again tested for drug release. It was observed that in one of the stress sample (150mg at stress and accelerated condition sample) there was dose dumping during dissolution process, where almost all the active in the formulation was released within few minutes of the dissolution process instead of prolonged and slow release. However, the batch under room temperature behaved similar in terms of drug release as compared to the initial analysis.
So, a discrepancy was found in the stress samples of the 150mg batch with respect to the drug release during in-vitro dissolution process. Hence, an analysis of the result and problem was undertaken to understand and if possible solve the problem.
It was found that the HCl used for wet granulation of the Bupropion HCl to stop its cyclisation has also degraded the polymer HPC HXF Pharm by hydroxylation reaction within the product during its storage for stability, resulted in breaking of the polymer Klucel® HXF Pharm grade. Thus resulted in dose dumping as opposed to providing sustained released. We consulted with the supplier of the excipient HPC Hercules Inc. (Aqualon) Dr. Tom Durig helped us for the investigation of viscosity and Gel Chromatography of Bupropion HCl SR formulation using other grades of HPC. Finally it was found using the lower molecular weight grade HPC EXF Pharm with more amount than the high molecular weight HPC-HXF Pharm grade. HPC EXF Pharm gave us the right formula with no dose dumping at the accelerated stability condition.
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Resource Person: Masihuddin J.
