A Tool to Optimize Formulations
By Remco van Weeren, PhD
Sr. VP Marketing and Technology, Bilcare Inc.
Dr. Ajith Sashidharan
VP Global Research Services, Bilcare Ltd.

Sensitivity of formulated drugs is often described qualitatively as highly sensitive or less sensitive based on the active ingredients properties. Therefore the difference in the sensitivity when changing formulations using the same active ingredients goes unnoticed. Formulation scientists would benefit if the small differences in the environmental sensitivity between the formulations were distinguishable giving them leads to optimize the formulation in terms of stability and other required properties. Often, a conventional stability study in the final packaging format is the only way to understand the sensitivity or stability of the product and leaves little or no opportunity for the formulator to optimize the formulation for better stability.

Forced degradation studies are popular in the preformulation stage, but these are more focused on the impurity profiling for analytical method development and to develop the moisture absorption isotherms. Since these studies are concentrated on the ingredient properties, strengths of final formulation with respect to environmental stability is not determined or clearly distinguished in these studies. A new sensitivity profiling method has been developed which looks at the final formulation beyond the chemical stability and diagnoses the external reasons for the deterioration of the characteristic properties of the formulation which is essential to serve its purpose for the patients. It quantitatively evaluates the effect of the environmental parameters on the deterioration of the product and looks not only at its chemical/assay properties, but also various physical properties, such as drug release patterns and the interaction with packaging materials. This method quantifies the various sensitivity parameters of the formulation in an absolute scale of 0 to 10 based on the results of forced degradation experiments and thus gives the formulators a tool to measure the strength of their formulation in a scientific scale prior to finalizing it.

Shortcomings of the conventional forced degradation /stress testing studies

There are no detailed regulatory guidelines that describe how to carry out stress testing and it is often used synonymously with accelerated testing. This is due to the fact that the purpose of both stress testing and accelerated stability testing is to create a path for the product degradation and not to diagnose the causes for degradation. These two tests should be distinctly different. For identifying the factors affecting degradation, it is essential to define the testing protocols in such a way that to be able to understand the cause and effect aspects while accelerating the degradation process, it is only necessary to increase the severity of the parameters causing deterioration. In fact the purpose of the accelerated stability studies is to fasten the degradation, while that of stress testing should be the understanding the degradation process.

The ICH defines accelerated testing as: Studies designed to increase the rate of chemical degradation or physical change of an active substance or drug product using exaggerated storage conditions as part of the formal, definitive, storage program. These data, in addition to long-term stability studies, may also be used to assess long-term chemical effects at non-accelerated conditions and to evaluate the impact of short-term excursions outside label-storage conditions such as might occur during shipping. Results from conventional accelerated studies are not always predictive of physical change. Stress testing is defined as: Studies undertaken to elucidate the intrinsic stability of the drug substance. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing.

From a regulatory perspective, stress testing or forced degradation studies are a scientific tool to understand stability issues, and are inherently predictive in nature. Accelerated testing on the other hand is purely focused on whether or not stability is maintained at a pre-set condition.

Sensitivity profiling through BilcareOptimaTM

It is essential to look at a formulation beyond the chemical aspects to ensure the efficacy of the product to the patient. As an example, a chemically stable product without any visual degradation over time or due to exposure to humidity/light condition is normally categorized as a stable product. However this product may not be effective, if its drug release property is affected by any environmental factor or if there is a tendency to liberate gases on storage. In conventional stability studies these factors are not studied critically, rather it is only assessed whether the determined values are within the specified limit at the end of the study.

BilcareOptima tests the final dosage form under a range of different conditions, aimed at determining the critical characteristics that affects the stability and quantify its severity on a scientific scale.

Three batches of dosage forms are studied under various environmental conditions for more precise understanding and the effect of the following parameters:

Hygroscopicity - Dehydration - Physical degradation - Chemical degradation - Drug release pattern - Hardness - Photo sensitivity as a function of RH and Temp - Gas liberation tendency - Product packaging material interaction. - Dimensional aspects.

Each of the properties are investigated for the influence of various environmental parameters and its impact on the stability and efficacy of the product. These evaluations lead to exact determination of the critical property of the given oral dosage form and influencing environmental parameter. It is further used to determine the threshold values and sensitivity scaling using a mathematical model. This information is used to predict the product behavior at different climatic condition and decide on the storage conditions, protection needs and shelf life.

The sensitivity scale gives a quantitative picture about the product sensitivity towards environmental parameters property wise. The property wise sensitivity data is allowed to come down to the most critical property
This also helps us to understand batch to batch and formulation to formulation variations and can be used to differentiate the two.

Formulation comparisons

Sensitivity profiling is a very effective tool to understand the difference in the stability of various formulations of the same ingredient and dosage. Normally, one often fails to identify the micro differences in the formulation and ends up generalizing the formulations. However when the micro details are studied in a scientific way, it helps to identify the differences and understand the formulation better.

A study was conducted on the various brands (and hence different formulation) of Ranitidine as per this method to understand the differences in hygroscopicty. Ranitidine is a highly hygroscopic product and qualitatively all Ranitidine tablets are rated in general as highly hygroscopic products without any differentiation.

As a standard practice, hygroscopicity of a product is measured in terms of equilibrium moisture content (or EMC).
EMC is the highest level of moisture content which a product can achieve at a specified condition. However in all probability, a product in protective packaging never reaches that stage during its shelf life. It is thus the absorption rate, nature and path of moisture absorption, and/or the effect of moisture under influence of temperature and light, that are the deciding factors for the stability in a packaged condition. These are seldom studied in the forced degradation studies and hence the performance of the formulations could not be predicted.

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Figures 1, 2 and 3 show the moisture absorption rate, EMC and nature of the absorption path of different Ranitidine formulations at 150 mg when exposed at 40 C and 75% RH.
It can be seen from these graphs that the EMC, absorption rate and the path all are distinctly different for the formulations.

This shows that with the same ingredients and dosage level, the products show different moisture absorption capabilities which indicates that the shelf life, storage conditions, and protection needs cannot be the same for all the formulations. This clearly puts a question mark to the accepted trend in the industry to follow the innovator or brand leader’s packaging selection for the generic formulations which are approved after patent expiration.

The differentiation of the formulation is very critical for its optimization and is possible only when each formulation is subjected to detailed sensitivity profiling.

There are also changes of behavior for similar formulations at different climatic conditions. The accelerated stability condition of 40C/75% RH is standard for all the protocols. As described in the introduction accelerated stability conditions only create a path for faster degradation, and are not predictive in nature of the product’s behavior in different climatic conditions, especially for higher humidity conditions. Increasing the severity of the testing condition is not the solution, as this is misleading and complicated. What is important is to understand the effect of each environmental parameter individually and in combination to ensure understanding of the degradation profile.

The following results show the effect of different climatic conditions on the hygroscopicity of a cefuroxime formulation.

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As can be seen in Figure 4, the EMC of the product at the 25/90 condition is significantly higher than at 40/75. Scientifically, it is reasonable to assume that at elevated temperatures the product undergoes simultaneous dehydration and hence EMC which is the equilibrium between the hydration and dehydration phenomena is lower. At lower temperatures, the dehydration process is negligible and hence the EMC levels are higher. This means that the product absorbs more moisture in high humidity areas than what we observed at accelerated conditions. 40/75 is the ICH “accelerated condition” while 25/90 is the standard condition for most of the coastal area in India and Mexico which means that the product deterioration could be significantly higher in these regions than anticipated from the results of the accelerated stability studies.

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Figure 5 shows that the rate of moisture absorption is influenced more by external humidity than temperature which is contrary to the logic of the accelerated condition where elevated temperature is used to increase the rate.

One of the major physical properties affected by moisture absorption is the hardness of the tablet. Reduction in hardness might not be very critical for a product packaged in bottles, but it is very critical for a product packaged in blister pack as the product needs to be pushed against the lid foil to break the lid to take the product. The hardness of the product cannot fall below the push through force (PTF) required to open the blister.

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As can be seen in Figure 6, when the hardness is measured after 12 hrs of exposure in different conditions, the decrease in hardness is more pronounced at lower temperatures than at accelerated temperature.
This again shows that even if the product hardness maintains the acceptable level on accelerated study protocols, it could indeed drop below its acceptable level at ambient temperature conditions and hence the correlation results from the accelerated studies cannot be extended for all climatic conditions.

Figure 7 shows a similar discrepancy when studying disintegration times under the various conditions. This property is one of the factors influencing the drug release property.

BilcareOptima is a forced degradation profile mapping protocol for a very quick determination of the critical parameters that determine the stability of a solid oral dose. It provides a quantitative picture about the sensitivity of important parameters towards the environmental factors which enable the formulator to predict its behavior when exposed to various environments.

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This tool can be used to map the sensitivities of various similar formulations, and understand the varied environmental dependencies of different formulations. In addition, it allows for a better prediction and understanding of stability than the standard accelerated testing protocol.