Simulations Plus

DDDPlus™: reimagine the in vitro dissolution experiment...

New in version 5!

  • Additional dosage forms: new models for coated beads, bilayer tablets, and delayed release coated tablets
  • Integration of the ADMET Predictor™ Module: now predict key physicochemical properties from chemical structure
  • Improved handling of bile salt effects on solubility in the biorelevant media
  • Upgraded 3D Parameter Sensitivity Analysis: assess the impact of changes to any combination of formulation and experimental parameters together
  • Various options for defining manufacturing properties: tensile strength and bonding constants can be added to predict disintegration
  • ... and more!

How should DDDPlus be applied?
  • Integrate with GastroPlus™ absorption/PBPK models to optimize formulations and generate mechanistic in vitro-in vivo correlations (IVIVCs) - better extrapolation of dissolution inputs for PBPK modeling
  • Assist with dissolution method development
  • Assess various formulation strategies to achieve a target in vitro dissolution profile
  • Apply virtual 'lot-to-lot' variability effects to help establish dissolution specifications - remove the guesswork associated with the identification of dissolution variability and its impact on PK exposure
What is DDDPlus?

DDDPlus, the industry's only in vitro dissolution software for formulation and analytical scientists, models and simulates the in vitro dissolution of active pharmaceutical ingredients (API) and formulation 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 or dissolution method.


Why is dissolution testing important?

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 in the development, characterization, and utilization process of both immediate and controlled-release formulations.

What are we simulating?

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 models the following dosage forms:

  • Powders
  • Capsules
  • Tablets
  • Polymer matrix (swellable and non-swellable)
  • NEW! Coated beads
  • NEW! Bilayer tablets
  • NEW! Delayed released coated tablets

DDDPlus allows you to select from one of 5 mathematical models to describe the dissolution of any ingredients included in the formulation. The mathematical models for the in vitro dissolution simulation account for the effects of:    

  • Manufacturing properties for the product (e.g., compression force, tensile strength, mean disintegration time)
  • Physicochemical properties of the formulation ingredients under study: pKa’s, aqueous solubility vs. pH, biorelevant solubility, diffusion coefficient, log D vs. pH, and density
  • Particle size distributions for each of the formulation ingredients
  • Interactions between the active ingredient and formulation excipients (e.g., solubilizers, disintegrants, wetting agents)
  • Microclimate pH-dependence of solubility and dissolution/precipitation
  • Differentiation between salt forms
  • Micelle-facilitated dissolution through the incorporation of surfactants in the media
  • Basic hydrodynamic effects, including different flow patterns and fluid velocities, for each experimental apparatus
  • ... and more!
When setting up your experiment, hydrodynamic effects are defined for the following systems:
  • USP Paddle
  • USP Basket
  • USP Flow Thru (closed and open loop options)
  • Rotating Disk
  • NEW! Pion µDiss Profiler™
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 do I use DDDPlus?

  • 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 are 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?
  • You need to develop a dissolution experiment which mimics a deconvoluted in vivo release profile. What experimental conditions are needed to generate a meaningful IVIVC/R (instrument type, speed, fluid volume, buffer composition, etc.)?
  • As you scale up manufacturing, you identify a certain level of variability in key formulation properties (e.g., dose, excipient content). How much 'lot-to-lot' variability are you allowed before you begin falling outside the defined dissolution specifications? And, how would these simulated profiles be translated to changes with the in vivo pharmacokinetics (PK)?

How does DDDPlus operate?

Single Simulation: based on compound properties (whether measured or predicted through the ADMET Predictor Module), formulation information, and in vitro dissolution setup, easily run a simulation to predict the time course changes in amount (or percent) dissolved for any ingredient in the product. Also track changes in microclimate and bulk pH levels vs. time.

Parameter Sensitivity Analysis ( PSA ): select any formulation or experimental parameters to assess the impact of changes on the in vitro dissolution vs. time profiles.


NEW! 3D PSA - now analyze the impact of changes in a 'design space' by simulating all combinations of any two selected parameters. Quickly identify an optimal combination which achieves the desired dissolution result.


Virtual Trials: run a series of simulations for different dissolution experiments, each of which is described by a random sample of formulation and/or 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 or experimental variables on the in vitro dissolution profiles, helping to establish critical dissolution specifications to meet certain regulatory guidelines. And, when coupled with GastroPlus models, you can begin to translate the dissolution variability to expected changes in pharmacokinetic profiles and assess virtual bioequivalence between formulation lots.


Optimization Module: calibrate your DDDPlus dissolution model using experimental in vitro dissolution vs. time data. Fit any combination of parameters to build your baseline model - once built and validated with existing data, use it to explore changes in formulation, experiment, and more!

Difference Factor 'f1' and Similarity Factor 'f2': The Difference Factor (f1) and Similarity Factor (f2) are recommended for dissolution profile comparisions in the FDA guidance for the industry. Once you run a simulation, you can load a reference profile and use the Difference Factor and Similarity Factor tools in DDDPlus to automatically run simulations across all formulation records and calculate the 'f1' and 'f2' values.



Tell me more about the model inputs...

Physicochemical Parameters


With DDDPlus, you can add as many excipients to the formulation (with one (1) API) as you like. This is done through the Formulation Composition interface.


NEW! ADMET Predictor Module: using the industry's #1-ranked Quantitative Structure-Activity Relationship (QSAR) models from our ADMET Predictor program, you can import chemical structures (as SMILES strings or .mol/.sdf formats) to predict the physicochemical properties required for DDDPlus. This can provide a quick, reliable foundation for your modeling activities.

NEW! DDDPlus now allows you to enter multiple excipients of the same type. Any custom ones can be entered, or your can use the database of commonly used excipients, provided with DDDPlus, where all necessary physicochemical properties are defined!


You can define multiple pKa ionization constants for each ingredient in your formulation. This information is used to define the aqueous solubility vs. pH profile and in the calculation of media pH during the simulation. Plus, the theoretical logD vs. pH curve is generated, which can be applied to estimate the bile salt solubilization effect when working with the biorelevant media (FaSSIF or FeSSIF).



For formulations where particle size is important, you can input either mean radius and standard deviation for the particle size distribution or load your own data (fractional or cumulative). DDDPlus comes with a tool to easily convert your cumulative particle size data (e.g., d(10), d(50), d(90)) into a full normal or log-normal distribution function.


Experimental Setup

In DDDPlus, you can define your dissolution method conditions, such as apparatus, speed, medium volume, and buffer, and the program will calculate the fluid velocity and use it to capture basic hydrodynamic effects on the dissolution rate.


Also, you can add as many experimental 'phases' as you like to mimic the in vivo environment. This can be helpful when trying to design an in vitro dissolution method to achieve a meaningful IVIVC.


DDDPlus has a sophisticated pH engine to calculate the dissolution media pH and solubility of each ingredient at the surface and bulk pHs. You can select from more than 90 built-in buffers, including all USP and biorelevant recipes, or easily design your own. You can also vary the concentrations of the different ingredients to create custom buffers at various pH.

Surfactants: add up to 2 surfactants per dissolution media. You have the option to choose from a list of several common surfactants or create your own.



NEW! Surfactant solubility tool: easily calculate the Critical Micelle Concentration (CMC) and/or surfactant enhancement factor provided you have selected a media with one or two surfactants. This applies to non-biorelevant surfactants like SDS, CTAB, BRIJ, CHAPS, etc.


This is exciting and I want to move forward! What's next?


Get started by requesting an evaluation. Or, if you are ready to reimagine your in vitro dissolution activities by incorporating modeling & simulation in-house, ask us for pricing information.