CHapter-11 Dissolution Software

Chapter-11 Pharmaceutical Dissolution Software

DDD Plus

Pharmaceutical Dissolution software;

What is DDDPlus?

DDDPlus (Dose Disintegration and Dissolution Plus) is an

advanced technology computer program that models and simulates

the in vitro dissolution of active pharmaceutical ingredients

(API) and formulation excipients dosed as powders, tablets,

capsules, and swellable or non-swellable polymer matrices

under various experimental conditions.

Dissolution rate is a critical parameter of pharmaceutical

dosage forms because the API needs to be dissolved before it

can be absorbed. In vitro dissolution testing is important to

screen formulations during development and to ensure batch-to-

batch quality control during production. Throughout the

world, more than 40 years of research have been devoted to

characterizing the biopharmaceutical properties of drugs.

Several guidelines have been published and all pharmacopoeias

include a description of dissolution testing.

During drug development, in vitro dissolution testing is an

important tool for evaluating candidate formulations and for

understanding possible risks related to specific

gastrointestinal factors, potential for dose dumping, food

effects on bioavailability, and interaction with excipients.

Today, dissolution studies are the most frequently used tools

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in the development, characterization, and utilization process

of both immediate and controlled-release formulations.

Dissolution, in the simplest sense, can be defined as the

sequence by which a solid solute enters into a solution in the

presence of a solvent. We can define the dissolution rate as

the amount of ingredient in a solid dosage form dissolved in

unit time under particular conditions.

A DDDPlus simulation is essentially the numerical integration

of a set of differential equations that coordinate well-

characterized physical actions that occur during dissolution,

including but not limited to changes in particle size

distributions for both active and excipient ingredients, as

well as changes in microclimate (surface) and medium bulk pH

as formulation constituents dissolve.

DDDPlus allows you to select from one of 5 mathematical models

and 5 dosage forms used to describe the dissolution of a

single ingredient. The mathematical models for the in vitro

dissolution simulation account for the effects of:

Physicochemical properties of the formulation ingredients

under study: pKa’s, solubility, diffusion coefficient,

and density.

Manufacturing properties for immediate release dosage

forms.

Particle size distribution for each of the formulation

ingredients.



Different flow patterns and fluid velocities for each

experimental apparatus.

Interactions between the active ingredient and

formulation excipients.

Microclimate pH-dependence of solubility and

dissolution/precipitation.

Micelle-facilitated dissolution through the incorporation

of surfactants in the media.

In spite of its sophistication, DDDPlus is relatively easy for

someone with a background in formulation and chemistry to

learn and use. DDDPlus incorporates an intuitive and modern

graphical user interface that enables rapid and smooth

transition from setting up inputs to evaluating results.

Outputs are displayed with immediate on-screen text and

graphics for single simulations, and can be saved to Microsoft

Excel-compatible tab-delimited ASCII text files for both

single and multiple simulations. Extended analyses through

Parameter Sensitivity Analyses and Virtual Trials provide

insight into the probable behaviors of formulations under

varying conditions and can guide experimental efforts to focus

precious resources where they will do the most good.

How Can DDDPlus be Used?

Formulation-Specific Model Building



You can use the Optimization Module within DDDPlus to quickly

build the own formulation-specific models based on the own

data. The term “model” here refers to a specific set of one

or more fitted parameters that determine the rate of

dissolution under varying conditions during an experiment.

Variables such as amounts of active pharmaceutical ingredient

(API) and excipients, and particle size distributions for

each, are accounted for in the dissolution equations. The

Optimization Module enables DDDPlus to calibrate itself to a

specific data set using a variety of user-selected parameters

and optimization criteria. The formulation-specific models so

derived can then be used to estimate the likely changes in

dissolution while varying excipient content, particle size

distribution, and experimental parameters. For example, you

may have a set of dissolution data for an active ingredient

that was formulated with a certain type of solubilizer. By

calibrating the “solubilizer effect” coefficient for one

solubilizer amount, you can then estimate the effects of

differing amounts of the same solubilizer on the active

ingredient’s dissolution.

Formulation Evaluation and Dissolution Method Design

Because DDDPlus allows the user to adjust a wide variety of

physicochemical and experimental parameters (e.g., instrument

speed, medium volume, buffer recipes), studies can be run to

afford the researcher an insight into the likely dissolution

behaviors as a result of a variety of excipient content and



formulation changes (e.g., particle size distributions, amount

of API, amount of excipients, and tablet compression force)

under a variety of experimental conditions.

Parameter Sensitivity Analysis ( PSA )

The Parameter Sensitivity Analysis feature in DDDPlus enables

the user to assess the sensitivity of predicted dissolution to

critical input parameters. For example, if a particular

ingredient indicates a relatively high sensitivity of

dissolution to estimated solubility but a relatively low

sensitivity to the estimated standard deviation of the

particle size distribution, you would know that it is

important to accurately measure solubility by experiment, but

that a reasonable estimate for the standard deviation might be

sufficient. You would also know that improvements to

solubility could have a substantial payoff, while improving

standard deviation would not. If the solubility used in the

simulation was actually determined by experiment (not an in

silico estimate), and the predicted dissolution was poor, you

would know to direct efforts toward improving the dissolution

rate in spite of the solubility of the API (e.g., by reducing

particle size, changing to a salt formulation, or adding rate-

enhancing excipients).



NEW! Virtual Trials

The Virtual Trials feature in DDDPlus runs a series of

simulations with different simulated dissolution experiments,

each of which is described by a random sample of formulation

and experimental parameters to mimic the variances expected

with actual formulations or experimental setups. This powerful

capability allows you to assess the combined effects of

variations in formulation and experimental variables on the in

vitro dissolution profiles, helping to establish critical

dissolution specifications to meet certain regulatory

guidelines.

System Requirements:

DDDPlus is designed to run on Pentium-class Windows NT 4.0-

Service Pack 6, Windows 2000, Windows XP, Windows Vista, and

Windows 7 computers. A minimum of 256 MB of RAM is

recommended for optimal performance.

Most modern Pentium machines with speeds of 133 MHz or faster

should be able to run DDDPlus; however, simulation software is

computationally intensive and always benefits from greater

speed and memory. On a 2.4 GHz Pentium 4 notebook computer

with 256 MB of RAM, DDDPlus executes a typical simulation in

1-10 seconds, depending on the complexity of the formulation

and experiment, and the number of bins used to represent

particle size distributions.



DDDPlus Screen Shots

With DDDPlus, you can add as many ingredients to the

formulation as you would like. This is done through the

Formulation Composition window shown below (where

carbamazepine is the active ingredient dosed with PVP acting

as a solubilizer):

Once you have entered the formulation information, the

environment in which the dissolution experiment will take

place needs to be specified. This is done on the Experimental

Setup tab shown below:



During the simulation, a dynamic calculation of microclimate

and bulk pH occurs as the ingredients in the formulation

dissolve. With DDDPlus, you can create a buffer with a

specific pH. This is done in the window below:



Once you have entered the required information, you can

run the simulation and view the output of many different

variables. An example as to the plotting options for

DDDPlus is shown below:

Software Used In Pharmaceutical Industry3


In addition to running simulations of in vitro dissolution

experiments, you can also run a Parameter Sensitivity Analysis

(PSA), where a particular parameter is varied in order to see

how “sensitive” it is to the ingredients’ total percent

dissolved. An example output plot at the end of a PSA run is

shown below:



A new feature added to DDDPlus is the Virtual Trials mode.

Virtual Trials enables you to see how much variability should

be expected if a particular experiment was run many times. In

real life, running the same experiment many times results in

different outcomes each time, because there are many variables

in both the dosage form and experiment that cannot be held

perfectly constant. An example output plot at the end of a

Virtual Trials run is show below:



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