Robustness dissolution

Figure 7 Behavior of two formulations of a poorly soluble, weakly basic drug (solubility characteristics shown in Figure 6) in media composed at two pHs—one to represent acidic conditions in the stomach, the other to represent the hypochlorhydric stomach. (A) Formulation with non-robust dissolution characteristics and (B) Formulation with robust dissolution characteristics.

The dissolution specification for prolonged-release dosage forms should cover a minimum of three points one to ensure that dose-dumping does not occur (early, typically 20-30% release), one to confirm compliance with the dissolution curve profile (around 50% release), and one to ensure that the majority of the dose has been released (often more than 80% released). The robustness of the test procedure should be considered (e.g., to temperature, pH, and rotational speed). 

The derivation and experimental verification of the MMHS model represented a significant accomplishment and a natural plateau for film models. To be sure, there are general criticisms of film models and more specific criticisms of the MMHS model [6], However, overall the MMHS model should be recognized as a robust but simply applicable model which serves to demonstrate how factors such as intrinsic solubility of the acid drug, ionization and pA of the drug, and concentration of the reactive base all contribute to increasing the dissolution rate and mass transfer. 

When performing dissolution testing, there are many ways that the test may generate erroneous results. The testing equipment and its environment, handling of the sample, formulation, in situ reactions, automation and analytical techniques can all be the cause of errors and variability. The physical dissolution of the dosage form should be unencumbered at all times. Certain aspects of the equipment calibration process may show these errors as well as close visual observation of the test. The essentials of the test are accuracy of results and robustness of the method. Aberrant and unexpected results do occur, however, and the analyst should be well trained to examine all aspects of the dissolution test and observe the equipment in operation. 

In general, it is preferable to choose excipients and processes for IR dosage forms that do not result in a formulation that requires a particular pH to function well. In the general population, the pH in the stomach is quite variable (see the subsection Choice of Dissolution Test Conditions for Quality Control ) and there is no guarantee that the dosage form will be exposed to acid, so dosage forms that require acid to facilitate release are unlikely to perform robustly in the clinical practice setting. 

As a result, if dissolution from formulations is studied exclusively under low pH conditions, the formulators are likely to be in for a rude shock when the results come back from the pharmacokinetic studies—poor and highly variable absorption is the order of the day for drugs that have been formulated without an eye to robustness of the release from the dosage form as a function of pH. Instead, it is recommended that a formulation be sought that can release the drug even when there is not enough acid in the stomach to provide a sufficient boost to the solubility or when the gastric residence time is short. 

To test the robustness of the formulation to variations in gastric pH, dissolution results should be obtained in both the pH 2 medium described in Table 3 and a model which reflects the conditions in the hypochlohydric stomach. A good choice would be acetate buffer adjusted to pH 5 and having a very low buffer capacity, since hypochlorhydria is generated by a reduction in HCl secretion rather than the addition of buffer species. 

For some products, e.g., propanolol extended release formulations (USP 27), a modification of the standard method for enteric-coated dosage forms have been introduced to reflect the change from conditions in the stomach to those in the small intestine. This is a step in the right direction, but to achieve dissolution testing that can differentiate between formulations which are robust and those which are not, and especially to be able to predict food effects on the release from... 

Development of a robust IVIVC is possible when absorption is limited by lumenal dissolution, provided lumenal dissolution (or release) is adequately simulated in vitro. 

Once the appropriate dissolution conditions have been established, the method should be validated for linearity, accuracy, precision, specificity, and robustness/ruggedness. This section will discuss these parameters only in relation to issues unique to dissolution testing. All dissolution testing must be performed on a calibrated dissolution apparatus meeting the mechanical and system suitability standards specified in the appropriate compendia. 

In comparison to the approach of Ginski et al. [48], the Miyazaki s method appears to be more elaborate and complex and is thus coming closer to the in vivo situation. The device can simulate various effects of pH on dissolution and is, as an open system, closer to in vivo conditions compared to a closed one. However, it exhibits the drawback of not freely adjustable pH values acting on the drug. Low flow rate in the dissolution vessel may limit applications of complete dosage forms and allows predominantly only the use of granules, pellets, or grinded tablets. Furthermore, the application of compendial dissolution devices appears to be a more robust approach. 

The approach of Kataoka et al. [54] shows some desirable features, such as downsized, in vivo relevant volumes, and low complexity of the device and thus low error proneness. However, the device lacks the possibility to add complete dosage forms and the use of compendial dissolution devices would be a more robust approach. 

The approach of Motz et al. [55, 56] can be seen as a combination of the approach of Ginski et al. [48] (compendial dissolution equipment) and the approach of Kobayashi et al. [50] (open dissolution module). The most dominant advantage may be seen in the application of complete dosage forms and the application flow rates resulting in physiologically relevant concentrations. Furthermore, the apparatus appears to be robust being equipped with compendial dissolution equipment. However, the apparatus is still lacking a pH simulation unit. 

When speaking about the optimisation of a (tablet) formulation then in most cases the attainment of preferable response values is meant, e.g. a high crushing strength, a low disintegration time, a certain dissolution profile etc. Another important desirable property of a formulation can be that the formulation is robust towards (small) deviations (errors) in process conditions or the proportions of the excipients this means that despite these errors the values of the responses considered remain at (almost) the same level or deviate with only an acceptable amount. It is of course desirable to maintain properties of any product on exactly the same value during production or use, but on the other hand this can be very expensive... 

Rotational Speed. The rotational speed of a basket or paddle is an important consideration in the development and validation of the dissolution test. A speed of 100 rpm is commonly used with the basket apparatus and a speed of 50 rpm is used with paddles. In method validation, one needs to ensure that slight variations in rotational speed will not affect the outcome of the dissolution test. The compendial limit for variations in rotational speed is 4%, but a wider variation (e.g., 10%) may be considered in testing the robustness of the method. 

To determine precision at multiple collection time points for the dissolution profile of a modified release formulation, normalization to the final time point (or infinite time point) will eliminate tablet-to-tablet and lot-to-lot variation. Figure 4.1 illustrates the way that normalization is used to remove tablet-to-tablet variation. However, the normalization technique should be used during development only as a means of investigation of the profile. The final formulation should be sufficiently robust to produce complete release at its final time point. Normalization to remove lot-to-lot variation can be performed using the following equation ... 

The stability of solutions of the complexes varies widely. Some adducts, such as [1 ( )( 3)2( 2- 60) 1] (13) [Eq. (13)], readily revert to starting materials on dissolution in certain solvents or on thermolysis, whereas others, such as [Os3(CO)10(PPh3)(T/2-C60)] [Eq. (14)] (32), are sufficiently robust that other ligands may be preferentially displaced ... 

Tablet hardness Tablet hardness is determined periodically throughout the batch to ensure that the tablets are robust enough for coating, packing, and shipping and not too hard to affect dissolution. 

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