Moisture-activated dry granulation: The 'one-pot' process - Pharmaceutical Technology

Latest Issue
PharmTech

Latest Issue
PharmTech Europe

Moisture-activated dry granulation: The 'one-pot' process


Pharmaceutical Technology Europe
Volume 22, Issue 3

This article is based on a two-part series of reports published in Pharmaceutical Technology in November and December 2009, respectively.

http://www.pharmtech.com/MADGpart1

http://www.pharmtech.com/MADGpart2


Creative Crop/Getty Images
Wet granulation, dry granulation and direct blending are the most popular granulation processes for solid dosage form manufacture in the pharmaceutical industry, but they each have distinct drawbacks. A moisture-activated drying granulation (MADG) process was described more than 20 years ago,1 but has not found widespread acceptance — perhaps because of its unusual simplicity coupled with uncertainty about equipment specifications and the manufacturing process.

The MADG process

MADG is a process in which moisture is used to activate granule formation, without the need to apply heat to dry the granules. During this process, the generation of moist agglomerates is followed by the stepwise addition and blending of common pharmaceutical ingredients that absorb and distribute the moisture, which results in a uniform, free-flowing and compactable granulation.

There are two major stages in MADG: agglomeration and moisture distribution/absorption.




During agglomeration, all or part of the drug is mixed with filler(s) such as lactose monohydrate and an agglomerating binder, such as povidone to obtain a uniform mixture. While mixing, a small amount of water is sprayed onto the powder blend, which moistens the binder and makes it tacky. The binder facilitates the binding of the drug and excipients as they move in a circular motion forced by the mixer impellers or blades. The resulting agglomerates are small and spherical because the amount of water used in MADG is much lower than in conventional wet granulation; thus preventing the agglomerates from forming large wet lumps. The particle size of the agglomerates generally falls in the range of 150–500 μm.

In moisture distribution/absorption, moisture absorbents, such as microcrystalline cellulose or silicon dioxide, are added while mixing continues. When they come into contact, the moisture absorbents pick up moisture from the moist agglomerates, resulting in moisture redistribution within the mixture. When this happens, the entire mixture becomes relatively dry. While some of the moisture is removed from the wet agglomerates, some of these agglomerates remain almost intact and some — usually the larger particles — may break up. This process results in granulation with more uniform particle size distribution.

The process continues with the addition of a disintegrant, such as crospovidone, to the mixture followed by blending for a few minutes. Then, while mixing, lubricant(s), such as magnesium stearate are added and blended for sufficient time to achieve adequate lubricity.

This completes the MADG granulation process.

Granule formation

The granule formation mechanism in MADG is the same as in conventional wet granulation. In both cases, it is a process of powder particle size enlargement, often in the presence of water and binders, through wet massing and kneading. The main differences between the two are the amount of granulating liquid used and the level of agglomeration achieved. In conventional wet granulation, substantially more water is utilised to create larger and wetter granules. This is then followed by heat drying to remove the excess water and milling to reduce the granule size.

In MADG, only a small amount of water is used to create agglomeration, followed by moisture distribution and absorption. Neither heat drying nor milling is required. Because the amount of water used in MADG is small (usually only 1–4% of the entire formulation), it is important that the water is delivered accurately and distributed uniformly during the agglomeration stage — this makes the selection of a spray system that provides accurate delivery and a well-defined spray pattern very important.

In terms of equipment, a high-shear granulator is more suitable for the MADG process, and an ideal machine should have efficient impellers/blades and choppers to allow good mass movement and proper mixing. It should also allow water to be sprayed only on the powder bed and not on the blades, choppers or granulator wall. Also, the blades and bowl configuration should be such that it does not allow "wet pockets" or "dead spots" to remain after the moisture distribution or absorption stage, which would then necessitate additional sizing and shifting of the granulation.


ADVERTISEMENT

blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
|Monthly
| Weekly

Survey
FDASIA was signed into law two years ago. Where has the most progress been made in implementation?
Reducing drug shortages
Breakthrough designations
Protecting the supply chain
Expedited reviews of drug submissions
More stakeholder involvement
Reducing drug shortages
70%
Breakthrough designations
4%
Protecting the supply chain
17%
Expedited reviews of drug submissions
2%
More stakeholder involvement
7%
View Results
Eric Langerr Outsourcing Outlook Eric LangerTargeting Different Off-Shore Destinations
Cynthia Challener, PhD Ingredients Insider Cynthia ChallenerAsymmetric Synthesis Continues to Advance
Jill Wechsler Regulatory Watch Jill Wechsler Data Integrity Key to GMP Compliance
Sean Milmo European Regulatory WatchSean MilmoExtending the Scope of Pharmacovigilance Comes at a Price
From Generics to Supergenerics
CMOs and the Track-and-Trace Race: Are You Engaged Yet?
Ebola Outbreak Raises Ethical Issues
Better Comms Means a Fitter Future for Pharma, Part 2: Realizing the Benefits of Unified Communications
Better Comms Means a Fitter Future for Pharma, Part 1: Challenges and Changes
Source: Pharmaceutical Technology Europe,
Click here