In this article we will learn about a systematic and modern approach to tablet product design.
The ANOVA approach involves making statistical comparisons of different tablet formulas. Each formula represents a different combination of excipients. The selection of a prototype formula is done by running an ANOVA on the results of all the tests performed;' The formula that is significantly better than the others tested becomes the prototype formula.
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Tablet product design requires two major activities-
● First, formulation activities begin by identifying the excipients most suited for a prototype formulation of the drug.
● Second, the levels of those excipients in the prototype formula must be optimally selected to satisfy all process /product quality constraints.
What is prototype formulation?
Formulation prototype development studies are designed and performed with attention to every detail, from use of excipients that are generally recognised as safe (GRAS) to identification and prevention of potential stability and processing problems that may be encountered during scale up manufacture
Formulation prototype development projects start with a strategic formulation plan. The formulation strategy is the result of a thorough analysis of the preformulation data report, the intended manufacturing process, any patient compliance issues and the strategic goals of the company.
Factors affecting tablet formulation
A. Factors Affecting the Type of Excipient Used in a Tablet Formula
The type of excipient used may vary depending on a number of preformulation, medical, marketing, economic, and process/product quality factors-
Pre formulation
Only those excipients found to be physically and chemically compatible with the drug should be incorporated into a tablet formula. Preformulation studies should also provide information on the flow and bonding properties of the bulk drug. Excipients that tend to improve on flow (glidants) and bond (binders) should be evaluated for use with poor-flowing and poor bonding compounds, respectively. At the conclusion of a preformulation study, it may be known which tableting process [direct-compression or granulation (wet/dry)] will be appropriate for the drug.
Direct compression is the preferred method of tablet manufacture for the following four major reasons:
(a) It is the cheapest approach since it is a basic two-step process (if components are of the proper particle size) , involving only mixing and compressing, and it avoids the most costly process of unit operating, drying.
(b) It is the fastest, most direct method of tablet production.
(c) It has fewer steps in manufacture and fewer formulation variables (in simple formulations).
(d) It has the potential to lead to the most bio available product (which may be critical if bioavailability is a problem).
Medical
The desired release profile for the tablet should be known early in tablet development. Immediate, controlled, and combinations of immediate and controlled release profiles require totally different approaches to formulation development.
Immediate release tablets usually require high levels of dis integrants or the use of superdisintegrants. Controlled release are usually formulations of polymers or wax matrices.
In many instances, the rate-limiting factor to absorption of a drug is dissolution. It may be necessary for the formulator to select excipients which may increase drug dissolution and enhance absorption.
Solvang and Finholt [ 7] studied the effect of binder and the particle size of the drug on the dissolution rate of several drugs in human gastric juice. Surface active agents such as sodium lauryl sulfate may be needed to promote wetting of the drug. Alternatively, the use of disintegrates or superdisintegrants may improve dissolution. Hydrophobic lubricants may be used only at low levels or not at all.
The targeting of drug delivery to various sites in the gastrointestinal tract is sometimes required to maximize drug stability, safety, or efficacy
Drugs that are acid labile or cause stomach irritation should not be released in the stomach .
The use of enteric coatings on tablets is the most common method of targeting the release of a drug in the small intestine. Tablets which are to be coated should be formulated to withstand the rigors of a coating process and to be compatible with the coating material. The use of alkaline excipients in the tablet may prove to weaken the integrity of the enteric coated tablet.
Marketing
The appearance of a tablet dosage form is usually not thought to have a large impact on the commercial success of a particular product. However, all tablets must meet a minimal elegance criteria
The appearance of a tablet can be evaluated by its color, texture, shape, size, and coating (when present), and any embossing information.
Tablet appearance can be affected by the color and texture each excipient brings to a tablet formulation. Lactose, starch, and microcrystalline cellulose appear white to off-white when compressed. The inorganic diluents such as calcium sulfate, calcium phosphate, and talc produce more of a gray color in the tablet. Drugs will impact on the overall color and appearance of the tablet.
Drug-excipient interactions may change the appearance of the tablet with time. The use of dyes may be required to improve the appearance of certain tablets. Relatively large amounts of stearates and high molecular weight polyethylene glycols produce glossy tablets
The tableting properties (flow and compressibility) of tablet formulations containing a low percentage of active ( < 100 mg) are primarily dictated by the tableting properties of the excipients in the formulation.
The formulator will frequently have numerous excipients to choose from because the drug does not dominate the behavior of the formulation during processing. However, if the tablet formula contains a large percentage of active, the formulator may be somewhat restricted in the choice of excipients.
In order to be easily swallowed and remain elegant, tablet size and weight is limited in these formulations. Tablet formulas with a higher percentage of active can contain only minimal quantities of excipients.
These excipients must therefore perform their functions at relatively low levels. The use of a more effective binder such as microcrystalline cellulose may be required to produce these tablets. Tablets with a high percentage of actives frequently require granulation methods of manufacture simply because excipients will not perform their desired function at low levels in a direct-compression method.
Marketing may request a coated tablet product. The quality of a coating on a tablet can be greatly affected by the tablet formulation onto which it is applied. Tablets with low resistance to abrasion (high friability) will result in coatings that appear rough and irregular. Coating adhesion can be greatly affected by the tablet excipients. Hydrophilic excipients can promote greater contact with the coating and result in superior adhesion. Hygroscopic excipients or drugs will cause swelling of a coated tablet and result in rupture of the film with time.
Embossing of compressed tablets is becoming increasingly popular. Embossing permits the tablet to have identifying information without requiring coating and printing operations. Embossing does exacerbate any picking or sticking problems usually observed during compression. This may necessitate higher levels of lubricants and glidant to alleviate these problems. Extreme care should be taken in designing tooling for embossed and scored tablets. It may take several design attempts to select a tooling design that will consistently produce acceptable embossed or scored tablets. Embossed tablets that are to be film-coated present additional coating problems such as bridging of the coat across a depression in a tablet.
Economics
One factor often overlooked in the development of a tablet formula is the cost of the raw materials and the process of manufacture. Direct compression is usually the most economical method of tablet production as previously discussed. In spite of the more expensive excipients used in direct compression, the cost (labor, energy, and time) of granulating is usually greater.
Some companies have preferred manufacturing processes and raw materials. These general manufacturing processes and materials are considered the first choice when developing a new product. If it is demonstrated that the preferred manufacturing process or materials are not suitable for a new product, then alternative processes or materials are used.
The use of preferred processes and materials helps keep the types of equipment needed to manufacture and materials in inventory at a minimum, thus reducing capital expenditures and material costs. Preferred manufacturing process and materials also makes it easier to automate a production facility for multiproduct use.
Process/Product Quality
Excipients should be selected that will enable the production of a tablet that will meet or exceed standard in-house quality tablet specifications.
A formulator should be involved in the establishment of tablet specifications and be able to provide sound rationale for the critical specifications. Typical tests performed on tablets are as follows:
- Weight variation
- Hardness- Friability- Disintegration time- Dissolution- Water content- Potency- Content uniformity
Product quality is most often addressed at the tablet development stage. However, it is also important to monitor the processing quality of a formulation during development.
Two reasons for monitoring processing quality during development are -
(a) to optimize the process as well as the product, and
(b) to establish in-process quality control tests for routine production.
It is more difficult to quantify the processing quality of a formulation than it is to measure the product quality. Some measurements that could be performed on the process include-
-Ejection force-Capping-Sticking-Take-off force-Flow of lubricated mixture-Press speed ( maximum)-Frequency of weight control adjustments-Sensitivity of formula to different presses Tooling wear-Effect of consolidation load (batch size)-Hopper angle for acceptable flow-Hopper orifice diameter for acceptable flow-Compressional forces-Environmental conditions (temperature, humidity, and dust)
Each of the above processing parameters can become a source of trouble in scale-up or routine production. By monitoring these parameters in development, it may be possible to adjust the formula or process early enough to alleviate the source of trouble.
The expected production output (numbers of tablets) per unit time will determine what speed tablet press will be required for a particular tablet product. If the anticipated unit output for a tablet product is expected to be large, a high-speed press will be required.
Attempts should be made in formulation development to design a tablet formula that will perform well on a high-speed press. A formula to run on a high-speed press should have excellent flow to maintain uniform die fill during compressing. It should have good bonding characteristics so that it can compress with a minimal dwell time.
Developing prototype tablet formula
B. Experimental Approach to Developing a Prototype Tablet Formula
After conducting an excipient compatibility study, a formulator may still have a wide choice of excipients available to use in the final tablet formula. The formulator must select a few excipients from a list of chemically compatible excipients. The formulator may later eliminate many drug-compatible excipients by selecting only those excipients known to provide a much needed function in the tablet formula as dictated by medical, marketing, economic, or process/product quality concerns.
The objective in screening excipients for a prototype tablet formula is to choose a combination of excipients that most completely achieves desirable tableting characteristics. Tablets made at this stage of experimentation can be made on a Carver/pulveriser, single-punch or rotary press depending on the amount of drug available. Obviously, no evaluation of the flow properties of a mixture can be made on a Carver or single-punch press.
The following is a list of several experimental tech• niques that may be used to assist the formulator to develop a prototype formula-
-Analysis of variance (ANOVA)-Statistical screening designs (first-order designs)-Plackett Burman-Extreme vertices
Statistical Screening Designs ( First-Order Designs)
Plackett Burman Designs
A statistical screening involves setting lower and upper limits on the levels of each excipient considered for use in a tablet formula. Usually no more than 10 excipients are being considered for use in the tablet at this point. An experimental design is chosen that will enable a statistical test for the effect of each excipient on each process/product quality
Optimizing prototype formula
- The term Optimize is “to make perfect”.
- It is defined as follows: choosing the best element from some set of available alternatives.
- An art, process or methodology of making something (a design, system, or decision) as perfect, as functional, as effective as possible.
WHY OPTIMIZATION IS NECESSARY ?
- Reduce the cost
- Save the time
- Safety and reduce
- Reproducibility
- Innovation and Efficacy
ADVANTAGES
- Yield the 'best solution' within the domain of study.
- Require fewer experiments to achieve an optimum formulation.
- Can trace and rectify 'problem' in a remarkably easier manner.
Optimizing prototype formula
C. Experimental Approach to Optimizing a Prototype Tablet Formula
A tablet formulation optimization study should be performed using an appropriately statistically designed experiment. Numerous experimental design texts [ 11, 12] are available that can assist a formulator in selecting the appropriate experimental design. The extreme vertices design is not recommended in most tablet optimization studies unless tablet weight is to be held constant.
It can be beneficial to have a statistician experienced in experimental designs select an appropriate design based on the established excipients and excipient ranges. All excipients should be varied in the optimization study to truly optimize the formulation.
Excipients levels are usually the only factors or variables in a formulation optimization study. To reduce the number of factors in a study, a ratio of two excipients can be used. However, the total quantity of those two excipients must be fixed in the formula.
When using excipient ratios as factors, include a factor for tablet weight.Tablet weight can then be varied as a factor. If a formulator suspects an interaction between an excipient and a particular process variable, the process variable should be considered for inclusion in the formulation optimization study. For example, in a sustained release direct compression tablet, compression force may impact on the release rate of the drug from the tablet. In this example, compression force should be included as a factor in a formulation optimization study. Usually, all other process variables are maintained constant.
Process variables that cannot be held constant but are not expected to impact on the tablet characteristics should be "blocked" appropriately in the design. For instance, different lots of raw materials or bulk drug may be used in an optimization study. The different lots should be treated as blocks in the experimental design. This will allow for a statistical test for block (lot) effect at the data analysis stage of the experiment. In this example, blocks serve as a flag to signal the formulator that the quality of the raw materials is not well controlled. Since the use of blocks do not "cost" the formulator any additional trials, blocks should be used wherever possible.
Statisticians experienced in experimental design frequently state that you cannot lose by blocking! It is important that all trails are performed in a randomized manner. After all the tablets have been manufactured, data analysis begins. A standard quadratic model is most often used to fit second-order experimental design data.
Commercially available software (XS TAT, STAT GRAPHICS, PCSAS, ECHIP) may be used to generate the coefficients and statistical tests on the raw data collected. This software will also provide a statistical analysis of the regression models produced. The analysis of the regression model provides the scientist information on how well the model explainer the data variation. If a particular regression model does not satisfactorily explain the data variation, transformations of the raw data can be tried to improve the fit of the model. For a regression model to be acceptable, the R 2 > 0. 75 the lack of fit should not be significant , and the residuals should have no more than a few outliers.
Once acceptable models have been established for each tablet characteristic, the scientist should examine the models to determine which main effects, interactions, or quadratic terms are significant. The formulator should then generate response surface plots of significant interactions as a function of the tablet characteristic. Response surface plots of significant main effects and quadratic terms will also help the formulator to understand the critical relationships between tablet characteristics and the formulation factors.
Optimization of the final formulation can be performed using commercially available software (X STAT, ECHIP, and PCSAS). Optimization invariably requires that constraints be placed on some or all of the critical response parameters.
Constraints may also be placed on some or all of the factors as well. One critical tablet characteristic must be selected to optimize ( minimize or maximize) while the other tablet characteristics and formulation factors are left constrained or unconstrained. For example. tablet friability could be constrained below 0. 3% while dissolution rate is maximized. The mathematical algorithm used in specific optimization routines (software) varies. Optimization algorithms used in software routines are usually based on a simple method or a grid search method.
The final formula determined to be optimal should be experimentally verified by manu facture and testing. Model predicted values for tablet characteristics should "agree" with actual experimental data collected on the optimal formula.
D. Establishment of Excipient and Preliminary Process Ranges
In light of the present interest in validating the product as well as the process of manufacture, it is to the formulator's advantage to establish excipient and process variable ranges. Having excipient and process ranges also allows production to make appropriate excipient or process changes with out prior notification of the regulatory agencies.
If it can be demonstrated that the excipient ranges used for conducting the optimization study produced acceptable tablets (i.e., all tablets produced were acceptable, then the excipient ranges used in the study should be used as final product ranges. However, if the excipient ranges used in the optimization study were not always acceptable, the ranges should be narrowed to acceptable limits. This can be done by performing constrained optimization of the critical response variables using registration specifica tions on the response variables as the constraining limits.
E. Bioavailability studies of tablet formulation
In vivo test procedures appropriate for tablets and other solid dosage forms are also the subject of Chapter 6 in Volume II of this series. In some cases in vivo testing of tablet formulations involves studies in animals prior to studies in humans: in other cases the tablet formulations are studied directly in humans.
When in vivo studies in humans are undertaken, it may be desirable or even essential to conduct such studies with more than one formulation. This is particularly true if a goal of product design is product optimization, and a primary objective is to maximize bioavailability or response versus time profile.
A bioavailability study should eventually be run comparing the optimized formulation, a formulation (within the excipient ranges) predicted to have the slowest dissolution, and a formulation (within the excipient ranges) predicted to have the fastest dissolution
The bioavailability study results can be used to establish a correlation between the in vitro dissolution test and the in vivo bioavailability parameters. If the three formulations(optimal, slow, and fast-dissolving) turn out to be bioequivalent, the excipient ranges are valid from the in vivo performance viewpoint. If the three formulations are not bioequivalent, then the excipient ranges should be tightened using the in vitro/in vivo correlation. The specifications for the dissolution of the tablet should be set based on this correlation.
Bioavailability Considerations
Before drugs can effectively pass through the gastrointestinal wall they must be in solution. Drugs which are only sparingly soluble in the gastro intestinal contents at or above the absorption site can have, as the controlling process affecting their absorption, the rate of drug solution in these fluids. In this type of system, the drug goes into solution at a slow rate ; absorption occurs almost immediately and is not, therefore, the rate limiting step. In one study, Nelson [ 17] correlated the blood level concentration of various theophylline salts with their dissolution rates.
As noted earlier in this chapter and throughout this volume, drugs which exert a systemic effect must dissolve as a prerequisite to effective drug absorption
The various processes of tablet making, including the aggregation of drug into granular particles, the use of binders, and the compaction of the system into a dense compact, are all factors which mitigate against a rapid drug dissolution and absorption in the gastrointestinal tract.
In considering in a general manner the availability of drugs from various classes of dosage forms, drugs administered in solution will usually produce the most available drug product-assuming the drug does not precipitate in the stomach or is not deactivated there.
The second most available form of a therapeutic agent would be drug dispersed in a fine suspension, followed by micronized drug in capsule form, followed by uncoated tablets, with coated tablets being the least bioavailable drug product in general. In formulating and designing drug products as well as in considering methods of manufacture, the fact that the tablet dosage form is one of the least bio available forms ( all other factors being equal) should be kept in mind.
Many factors can affect drug dissolution rates from tablets, hence possibly drug bioavailability-including the crystal size of the drug; tablet disintegration mechanisms and rates; the method of granulation; type and amount of granulating agent employed; type, amount, and method of incorporation of disintegrates and lubricants; and other formulation and processing factors.