DDDPlus 4.0

simulationsplus,inc.

Dose Disintegration

and Dissolution

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Simulate in vitro disintegration and dissolution of dosage forms under various experimental conditions

• Assist with dissolution method development

• Assess various formulation strategies to

achieve a target dissolution profile

• NEW! Apply variability effects of formulation

or experiment to help establish dissolution

specifications

DDDPlus™. . . The industry’s only in vitro dissolution software for the formulation scientist.

DDDPlus (Dose Disintegration and Dissolution Plus) is an advanced

computer program for formulation scientists to simulate the in vitro

disintegration and dissolution of active pharmaceutical ingredients (API)

and excipients under various experimental conditions. For new API, a single

calibration experiment is all that is needed, after which DDDPlus will

predict how changes in formulation or experimental parameters will

affect the dissolution rate. With DDDPlus, you no longer have to rely

on ‘cut and try’ methods to finalize a formulation design.

DDDPlus models 5 dosage forms• Powder

• Capsule

• Tablet

• Polymer Matrix (Swellable)

• Polymer Matrix (Non-Swellable)

4 USP experimental apparatus• USP Paddle

• USP Basket

• Rotating Disk

• USP Flow Thru

(closed and open loop options)

DDDPlus Inputs• Physicochemical Properties For Each Formulation Ingredient

- pKa’s, Solubility, Diffusion Coefficient, Particle Density

• Manufacturing Properties

- Compression Force & Diameter (For Tablets)

- Matrix Geometry and Dimensions (For Polymer Matrices)

• Particle Size Distribution

• Experiment Apparatus

• Dissolution Media (create or select from more than 90 built-in buffers,

including FaSSIF or FeSSIF)

• Select either bulk pH or microclimate pH for solubility calculation

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What is DDDPlus™?

5 mathematical models for dissolution• Mass Transfer

• Nernst-Brunner

• Intrinsic Dissolution

• Johnson-Cylindrical

• Johnson-Spherical

Model critical dissolution parameters• Particle size distribution

• Amount of excipients

• Dissolution media and surfactants

• Matrix dimensions and more….

Simulations Plus, Inc. • www.simulations-plus.com • Tel: (661) 723-7723 • Fax: (661) 723-5524

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How Do I Use DDDPlus™?

Simulation Outputs

• In early stage development, sufficient amounts of compound are not available for repeated conventional testing. What would be the expected dissolution profile for an initial formulation?

• You make your first formulation for a new compound, and dissolution is too slow. What can you change to make it acceptable?

• You’re asked to develop a formulation for a low solubility compound. You run one experiment with powder that does not dissolve fast enough. What can be done to produce the desired dissolution rate – micronization, solubilizer, wetting agent, or some combination?

• A dissolution experiment produces unexpected results. You suspect human error, but what best explains the data (buffer composition, instrument speed, fluid volume, etc.)?

• You need to develop a dissolution experiment that mimics a deconvoluted in vivorelease profile. What experimental parameters are needed (instrument type, fluid volume, instrument speed, buffer composition, etc.)?

Find answers to these questions and more with DDDPlus!

How do I use DDDPlus?

Parameter Sensitivity Analysis (PSA), where

several parameters are varied in order to see

how “sensitive” the active ingredient’s total

percent dissolved and dissolution-time

profile are to changes in each parameter.

Single simulations display formulation

ingredients’ total percent dissolved vs. time.

The solid lines represent the simulated

dissolution profile, and the dotted lines

represent the experimental data. You have

the ability to plot the amount dissolved or

undissolved in individual radii bins, amount

disintegrated, bulk pH and microclimate pH

of the dissolution media, and particle size

distribution.


Predict the effect of changes in particle size distribution to the formulation

Hydrocortisone coarse particles with slower dissolution rate

Hydrocortisone fine particles with fasterdissolution rate

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Virtual Trials

Particle Size Distribution


Mean Radius = 17.94 microns, Standard Deviation = 2.4, Number of Bins = 16.

Mean Radius = 5.35 microns, Standard Deviation = 2.4, Number of Bins = 16

The Virtual Trials feature runs a series of simulationswith different simulated dissolution experiments, each of which is described by a random sample offormulation and experimental parameters to imitate the variances expected with actual formulations orexperimental setups. This powerful capability allows you to assess the combined effects of variations informulation and experimental variables on the invitro dissolution profiles, helping to establish dissolution specifications.

With DDDPlus, you can add as many ingredients to the formulation as you would like. This is done through theFormulation Composition window shown below (where Adinazolam is the active ingredient, with HPMC K4Macting as a polymer and Lactose acting as other/filler).

DDDPlus has an optimization module that calibrates a drug’s dissolution rate using a single experimental data set.

You can add ingredients to the formulation andenter their physicochemical properties.

You can either input mean radius and standarddeviation for the particle size distribution or loadyour own sieve distribution data.

With DDDPlus, you can enter multiple pKa’sfor the ingredients. This information is usedin the calculation of media pH and solubilityduring the simulation.

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Physicochemical Parameters


With DDDPlus, you can define your experimental conditions like apparatus, instrument speed, medium volume

and medium type. DDDPlus calculates the fluid velocity automatically based on the instrument speed and

apparatus type.

Choice of 4 apparatus:

• USP Basket

• USP Paddle

• USP Flow Thru (closed loop and open loop)

• Rotating Disk

You can add as many experimental phases asyou want to better mimic your in vivo profile.

Shown to the left is a 2-Phase experiment.

Shown to the right is the simulatedprofile for the corresponding 2-Phaseexperiment. Ondansetron has a basicpKa of 7.43, and at phase 2 the pH ofmedia is set to 7.5, which reflects theprecipitation seen in this simulation.

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Experimental Conditions and Multi-Phase Experiments


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Dissolution Media and Microclimate pH

Microclimate pH

Surfactants

DDDPlus has a sophisticated pH engine to calculate the dissolution media pH and the solubilities of each

ingredient at the surface and bulk pH. You can select from more than 90 built-in buffers or design your own.

Shown is a USP Phosphate Buffer at pH 7.4. You can vary

the concentrations to create buffers at various pH.

During the simulation, the DDDPlus pH engine

calculates the bulk and microclimate pH as the

ingredients dissolve.

DDDPlus calculates the microclimate pH (pH at the diffusion

layer of the particle) for each ingredient in the formulation. You

can select either “microclimate pH” to calculate the solubility of

the ingredient at the diffusion layer or “bulk pH” for solubility in

the dissolution media.

DDDPlus allows you to add up to 2 surfactants per

dissolution media. Shown below is a screenshot of

the surfactants included in the FaSSIF buffer. Eleven

common surfactants are built-in. You can also define

new ones!

Now includes FaSSIF and FeSSIF buffers!


Polymer Matrix Dimensions

Difference Factor ‘f1’ and Similarity Factor ‘f2’

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The physical dimensions are critical parameters for polymer matrix

formulations. The Surface Area and Porosity parameters determine the

rate of hydration.

With DDDPlus you can select from 6 geometries:

• Biconvex

• Cylinder

• Oblong

• Sphere

• Torus

• User

The Difference Factor ‘f1’ and Similarity Factor ‘f2’ are recommended for dissolution profile comparisons in the

FDA guidance for the industry. Once you run a simulation, you can load a reference profile and compare to the

simulated results.

A profile with f1 value closer to zero is

considered similar.

A profile with f2 value greater than 50

is considered similar.

Rev. 6/9/11

simulationsplus,inc. 42505 10th Street West • Lancaster, CA 93534-7059 • U.S.A. • phone: 661-723-7723fax: 661-723-5524 • e-mail: [email protected] • web site: www.simulations-plus.com •NASDAQ:SLP

DDDPlus 4.0

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