DDDPlus 4.0
description
Transcript of 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.
Simulations Plus, Inc. • www.simulations-plus.com • Tel: (661) 723-7723 • Fax: (661) 723-5524
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
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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
Simulations Plus, Inc. • www.simulations-plus.com • Tel: (661) 723-7723 • Fax: (661) 723-5524
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
Simulations Plus, Inc. • www.simulations-plus.com • Tel: (661) 723-7723 • Fax: (661) 723-5524
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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!
Simulations Plus, Inc. • www.simulations-plus.com • Tel: (661) 723-7723 • Fax: (661) 723-5524
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