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On-Demand Manufacturing of Direct Compressible Tablets: Can Formulation Be Simplified?

Abstract

Purpose

Oral direct compressible tablets are the most frequently used drug products. Manufacturing of tablets requires design and development of formulations, which need a number of excipients. The choice of excipients depends on the concentration, manufacturability, stability, and bioavailability of the active pharmaceutical ingredients (APIs). At MIT, we developed a miniature platform for on-demand manufacturing of direct compressible tablets. This study investigated how formulations could be simplified to use a small number of excipients for a number of different API’s in which long term stability is not required.

Method

Direct compressible tablets of five pharmaceutical drugs, Diazepam, Diphenhydramine HCl, Doxycycline Monohydrate, Ibuprofen, and Ciprofloxacin HCl, with different drug loadings, were made using direct compression in an automated small scale system.. The critical quality attributes (CQA) of the tablets were assessed for the quality standards set by the United States Pharmacopeia (USP).

Results

This miniature system can manufacture tablets - on-demand from crystalline API using the minimum number of excipients required for drug product performance. All drug tablets met USP quality standards after manufacturing and after 2 weeks of accelerated stability test, except for slightly lower drug release for Ibuprofen.

Conclusions

On-demand tablets manufacturing where there is no need for long term stability using a flexible, miniature, automated (integrated) system will simplify pharmaceutical formulation design compared to traditional formulations. This advancement will offer substantial economic benefits by decreasing product time-to-market and enhancing quality.

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Abbreviations

API:

Active pharmaceutical ingredient

AV:

Acceptance value

BCS:

Biopharmaceutics classification system

CIPRO:

Ciprofloxacin HCl

CQA:

Critical quality attributes

DARPA:

Defense Advanced Research Project Agency

DC:

Direct compression

DIA:

Diazepam

DPH:

Diphenhydramine HCl

DOX:

Doxycycline monohydrate

FT:

Freeman technology

ffc:

Flow function coefficient

GIT:

Gastrointestinal tract

GMP:

Good manufacturing practice

HPLC:

High performance liquid chromatography

IBU:

Ibuprofen

MCC:

Microcrystalline cellulose

MIT:

Massachusetts Institute of Technology

NF:

National formulary

PAT:

Process analytical technologies

QbD:

Quality-by-design

Q value:

Percentage of label claim of drug dissolved

RH:

Relative humidity

RSD:

Relative standard deviation

SMCC:

Silicified microcrystalline cellulose

t80 :

Time it takes for 80% of the drug to dissolve

USP:

United States Pharmacopeia

UV:

Ultraviolet

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Correspondence to Allan S. Myerson.

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Azad, M.A., Osorio, J.G., Wang, A. et al. On-Demand Manufacturing of Direct Compressible Tablets: Can Formulation Be Simplified?. Pharm Res 36, 167 (2019). https://doi.org/10.1007/s11095-019-2716-2

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KEY WORDS

  • direct compressible tablets
  • formulation simplification
  • integrated pharmaceutical manufacturing
  • on-demand manufacturing
  • oral solid dosage