ZoomLab™ offers tremdendous benefits to your formulation process:
The tabletability (i.e., compressibility and compactibility) is assessed by preparing and analyzing tablets of the neat active ingredient (i.e., without any excipients). Alternatively, if the active ingredient is poorly compressible, it is possible to combine the active ingredient with a directly compressible excipient (e.g., microcrystalline cellulose). To do the experiment, an appropriate amount of powder is filled into the die of a manual hydraulic press (e.g., 300 to 500 mg, depending on the bulk density of the active ingredient and the diameter of the die); alternatively, a compaction simulator can be used. It is recommended to prepare five tablets at five different compression force levels (e.g., 4, 8, 12, 16 and 20 kN). Flat-faced punches without beveled edges should be used; the punch diameter should be between 8 and 12 mm. To facilitate ejection of the tablets, the punch surfaces and the die should be lubricated with magnesium stearate. To run the tool, the true density of the active ingredient, the punch diameter, the compaction force levels, the weight of the prepared tablets, their thickness and diameter, and the determined breaking force need to be entered. ZoomLab™ calculates the compaction pressure, the porosity of the prepared tablets, and their tensile strength. The compaction pressure (compressibility profile) and tensile strength (compactibility profile) are plotted against the porosity.
A modified version of the Gurnham equation is used to model porosity as a function of the applied pressure:
ln P = ln P_{0} - k_{c} ⋅ ε(P)
in which P is the compaction pressure, P_{0} is the compaction pressure at zero porosity, k_{c} is the compressibility resistance, and ε is the porosity.
The Ryshkewitch-Duckworth equation is used to describe the change in tensile strength with changing density:
ln T = ln T_{0} - k_{b} ⋅ ε(P)
in which T is the tensile strength, T_{0} is the tensile strength at zero porosity, k_{b} is the bonding capacity, and ε is the porosity. A least squares fitting is done to determine the compaction pressure at zero porosity, the compressibility resistance, the tensile strength at zero porosity, and the bonding capacity.
References
G.K. Reynolds, J.I. Campbell, R.J. Roberts, A compressibility based model for predicting the tensile strength of directly compressed pharmaceutical powder mixtures, International Journal of Pharmaceutics, 531 (2017) 215-224.
The content uniformity of pharmaceutical dosage forms can be affected by the particle size and size distribution of the active ingredient. With ZoomLab™, it is possible to set particle size limits for a given dose and eliminate problems of content uniformity associated with particle size. A modified version of the Yalkowsky-Bolton equation is used to calculate the relative standard deviation of the dose for a given particle size distribution. The theory assumes homogeneous mixing and that the particle size distribution is log-normal.
ZoomLab™ calculates the maximum volume median particle diameter (d50 value) predicted to pass the content uniformity test at stage I with the given confidence level (p-value) as a function of the distribution width (d90 / d50). It is possible to estimate the necessary particle size to ensure content uniformity criteria are met. The tool also demonstrates that the maximum acceptable d50 value increases significantly, if the width of the particle size distribution is reduced. For example, by narrowing the distribution width (d90 / d50) from 4 to 2, the acceptable d50 value increases about fourfold. Since larger particles impact content uniformity to a much greater extent, eliminating large particles (e.g., by sieving) can significantly alter the required particle size.
References
B.R. Rohrs, G.E. Amidon, R.H. Meury, P.J. Secreast, H.M. King, C.J. Skoug, Particle size limits to meet USP content uniformity criteria for tablets and capsules, Journal of Pharmaceutical Sciences, 95 (2006) 1049-1059.
To estimate the processability of powders, ZoomLab™ considers 14 different parameters. The parameters are grouped into the following categories: processability (mean value of all parameters), particle size (mean value of d10 value, d50 value, d90 value and distribution span), powder density (mean value of bulk and tapped density), powder flow (mean value of compressibility index, Hausner ratio and angle of repose) and tabletability (mean value of compaction pressure at a porosity of 0.15, tensile strength at a porosity of 0.15, tensile strength at 100 MPa compaction pressure, tensile strength at 150 MPa compaction pressure and tensile strength at 250 MPa compaction pressure). All parameters are scaled from 0 to 10, where 0 means “insufficient” and 10 means “excellent”; 5 is the acceptance value for direct compression. The parameters and their limits build on the Manufacturing Classification System, a tool for formulation scientists to rank the feasibility of different processing routes for the manufacture of solid oral dosage forms. All parameters can be determined by compendial methods, except for the last four parameters characterizing the tabletability of the powder.
Parameter | 0 | 5(=AV) | 10 | |
Particle size | d10 Value | 0 µm | 50 µm | 100 µm |
d50 Value | 0 µm | 75 µm | 150 µm | |
d90 Value | 1700 µm | 1000 µm | 700 µm | |
Distribution span | 4.0 | 3.0 | 1.0 | |
Powder density | Bulk density | 0.0 g/ml | 0.5 g/ml | 1.0 g/ml |
Tapped density | 0.0 g/ml | 0.5 g/ml | 1.0 g/ml | |
Flowability | Compressibility index | 40 | 25 | 10 |
Hausner ratio | 1.60 | 1.35 | 1.10 | |
Angle of repose | 65° | 45° | 25° | |
Tabletability | Compaction pressure at ε = 0.15 | 2000 MPa | 250 MPa | 0 MPa |
Tensile strength at ε = 0.15 | 0.0 MPa | 1.0 MPa | 8.0 MPa | |
Tensile strength at 100 MPa | 0.0 MPa | 1.0 MPa | 8.0 MPa | |
Tensile strength at 150 MPa | 0.0 MPa | 1.5 MPa | 12.0 MPa | |
Tensile strength at 250 MPa | 0.0 MPa | 1.5 MPa | 12.0 MPa |
All 14 parameters are shown in a radar chart. The radar chart can be used to quickly estimate the risk of different processing routes for tablets. In general, it can be concluded that the processability is improving, as the area circumscribed by the curve is increasing. Direct compression is possible if the parameters processability, powder flow and tabletability are greater than or equal to 5.0; dry granulation (e.g., roller compaction, slugging etc.) is possible if the tabletability parameter is greater than or equal to 5.0; wet granulation (e.g., fluid-bed or high-shear granulation) is always possible.
References
J.M. Suñé-Negre, P. Pérez-Lozano, M. Miñarro, M. Roig, R. Fuster, C. Hernández, R. Ruhí, E. García-Montoya, J.R. Ticó, Application of the SeDeM Diagram and a new mathematical equation in the design of direct compression tablet formulation, Eur. J. Pharm. Biopharm., 69 (2008) 1029-1039.
M. Leane, K. Pitt, G. Reynolds, and the Manufacturing Classification System (MCS) Working Group, A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms, Pharm. Dev. Technol., 20 (2015) 12-21.
G.K. Reynolds, J.I. Campbell, R.J. Roberts, A compressibility based model for predicting the tensile strength of directly compressed pharmaceutical powder mixtures, International Journal of Pharmaceutics, 531 (2017) 215-224.
ZoomLab™ predicts the processability of powder blends (i.e., combinations of an active ingredient with a filler / binder) from single-component data by applying proprietary mixing rules. The properties of the active ingredient are entered (Please note: It is not required to disclose the identity / structure of the active ingredient); the properties of more than 50 excipients and excipient blends are stored in a database. The tool can be used to identify suitable excipients and/or optimize an existing formulation.
To estimate the particle size distribution of the powder blend, the cumulative size distributions of the individual components are reconstructed from their d10, d50 and d90 values (it is assumed that the particles are spherical and log-normally distributed). The cumulative size distribution of the powder blend is then derived from the volume-weighted arithmetic mean of the individual curves. Bulk and tapped density of the powder blend are obtained from the weighted arithmetic mean of the individual values. In case of the bulk density, more weight is given to the component with the smaller bulk density; in case of the tapped density, more weight is given to the component with the larger tapped density. A very similar approach is used to predict the angle of repose of the powder blend. The angle of repose is calculated from the weighted arithmetic mean of the individual values (+ empirical weighting factor). To predict the compressibility profile of the powder blend, the profiles of the individual components are reconstructed from the intercept and slope of the curves. The porosity of the powder blend is then obtained from the volume-weighted arithmetic mean of the individual values. The compactibility profiles of the individual components are reconstructed from the intercept and slope of the curves. The tensile strength of the powder blend is then obtained from the volume-weighted geometric mean of the individual values. With this information, it is now possible to predict the processability of drug-excipient mixtures, if the properties of the individual components are known.
References
J.M. Suñé-Negre, P. Pérez-Lozano, M. Miñarro, M. Roig, R. Fuster, C. Hernández, R. Ruhí, E. García-Montoya, J.R. Ticó, Application of the SeDeM Diagram and a new mathematical equation in the design of direct compression tablet formulation, Eur. J. Pharm. Biopharm., 69 (2008) 1029-1039.
M. Leane, K. Pitt, G. Reynolds, and the Manufacturing Classification System (MCS) Working Group, A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms, Pharm. Dev. Technol., 20 (2015) 12-21.
G.K. Reynolds, J.I. Campbell, R.J. Roberts, A compressibility based model for predicting the tensile strength of directly compressed pharmaceutical powder mixtures, International Journal of Pharmaceutics, 531 (2017) 215-224.
The Formulation Wizard identifies suitable excipients and calculates potential starting formulations. The current version of the wizard supports the development of conventional uncoated tablets (dosage form ‘Tablets’, release kinetics ‘Instant release’, category ‘Conventional tablets’, no coating) by direct compression. Support for additional dosage forms and manufacturing technologies will be added in the future. To run the wizard, the user needs to define a target profile, enter the properties of the active ingredient, and select the preferred excipients. The wizard calculates the weight fraction of the active ingredient based on the given dose and tablet weight; 7% are subtracted from the tablet weight to accommodate the disintegrant and lubricant. In the next step, the wizard predicts the processability of all possible active ingredient-excipient combinations. The properties of the powder blends (i.e., particle size distribution, bulk density, tapped density, angle of repose, compressibility and compactibility profile) are estimated from single-component data by applying proprietary mixing rules.
Once all filler-binder combinations have been tested, the wizard sorts the tested excipients according to their performance. For this purpose, a weighted mean of all 14 parameters is calculated. More weight is given to tabletability and powder flow; particle size and powder density are less important. Filler-binder combinations with insufficient flowability and/or tabletability (values less than 5.0) are sorted out. All excipients and excipient blends are rated on a scale from zero (“not qualified”) to five stars (“most qualified”). “Five stars” denotes filler-binder combinations with the highest performance; “one star” denotes combinations with the lowest performance; “zero stars” means that the combination is not qualified.
In the last step, the wizard calculates a starting formulation with the selected filler-binder combination. A superdisintegrant is added; the amount depends on the selected filler-binder combination. For example, if the filler-binder combination already contains a disintegrant (e.g., ready-to-use excipients), the amount of superdisintegrant is reduced accordingly. If the tabletability of the powder blend is medium (value less than 6.0), a superdisintegrant with binding properties is chosen (e.g., Kollidon® CL-SF); otherwise, a regular superdisintegrant (e.g., Kollidon® CL-F) is added. Sodium stearyl fumarate is added as a lubricant; the amount depends on the selected filler-binder combination. In contrast to magnesium stearate, sodium stearyl fumarate does not cause overlubrication; it shows less incompatibilities with active ingredients. Once the correct amounts of superdisintegrant und lubricant have been determined, the amount of the filler-binder combination is recalculated. In addition the wizard provides detailed manufacturing instruction and tips for trouble shooting.
References
J.M. Suñé-Negre, P. Pérez-Lozano, M. Miñarro, M. Roig, R. Fuster, C. Hernández, R. Ruhí, E. García-Montoya, J.R. Ticó, Application of the SeDeM Diagram and a new mathematical equation in the design of direct compression tablet formulation, Eur. J. Pharm. Biopharm., 69 (2008) 1029-1039.
M. Leane, K. Pitt, G. Reynolds, and the Manufacturing Classification System (MCS) Working Group, A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms, Pharm. Dev. Technol., 20 (2015) 12-21.
G.K. Reynolds, J.I. Campbell, R.J. Roberts, A compressibility based model for predicting the tensile strength of directly compressed pharmaceutical powder mixtures, International Journal of Pharmaceutics, 531 (2017) 215-224.