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Technical papers

Understanding the differences between lactose grades in terms of powder flow

This paper presents the characterization of different types of lactose grades in terms of their physical properties related to powder flow. The flowability of powders and lactose grades in particular should be diligently assessed in relation to their function in a formulation or towards processing.

Adequate flow properties of direct compression excipients

Controlling powder flow is key to the success of many industrial processes. In the pharmaceutical industry, adequate powder flow is a prerequisite for weightcontrol during tablet manufacturing. Poor powder flow of the excipient in a formulation will lead to uncontrolled variations in tablet weight, poor content uniformity and inconsistent tablet properties. Poor flowing formulations can lead to under- utilization of fast speed tableting machines. To investigate the powder flow versus the tablettability of excipients in time, six excipients were characterized and tableted.

Content Uniformity of Direct Compression tablets

Direct compression is the simplest way of making tablets, requiring only blending and tableting operations for low and medium dose APIs where the tabletingproperties are primarily conferred by excipients. In order to make satisfactory tablets by direct compression, especially when the API dose is low, it is necessary to understand the factors that contribute to achieving acceptable drug content uniformity. These may be summarised as drug particle size, mixing strategy and selection of key excipients (filler-binders). This guide discusses these three factors, and is illustrated with data from DFE Pharma’s laboratory.

Amorphous lactose origins

The presence of amorphous lactose in predominantly crystalline materials has several origins. It could either be created deliberately as is the case in spraydried grade lactoses where it has an important function in the properties. Or it is created during processing of lactose during crystallization and milling processes. There are several techniques to assess the amorphous content, but they all have there own advantages and disadvantages.

Designing inhalation grade lactose

Blending a fine fraction with a coarse fraction of lactose can control the different physical properties i.e. the fines content in inhalation grade lactose. Detailed knowledge is obtained to predict various physical parameters of the lactose for inhalation out of fine and coarse lactose fractions. The example above is just one of a number of ways that the fines can be adjusted to give a specific result. The choice of fines can be a critical decision point in the development of a DPI.

Primellose® in ODT

In orally disintegrating tablets, the excipients of choice in direct compression are mannitol as filler binder and crospovidone as the superdisintegrant. An alternative superdisintegrant, Primellose®, is produced from natural resources in contrast to some other superdisintegrants. Here we show that Primellose® (croscarmellose sodium) gives fast disintegration of tablets.

Directly compressible lactose

Lactose monohydrate in a fine form can be compressed into hard tablets, but it exhibits poor flow. The goal of the secondary processes that convert lactoseinto directly compressible grades is to maintain the inherent compressibility of fine lactose, whilst improving the flow. This is done by three means:

Introduction to tableting by direct compression

Direct compression (DC) is by far the simplest means of production of a pharmaceutical tablet. It requires only that the active ingredient is properly blendedwith appropriate excipients before compression. Apart from simplicity of formulation and manufacture, the key advantages of direct compression include reduced capital, labour and energy costs for manufacture and the avoidance of water for granulation for water sensitive drug substances. This guide describes the scope and first principles involved in formulation of tablets by direct compression.

Introduction to tableting by wet granulation

Most pharmaceutical tablets are processed by wet granulation, and yet it is the most complex means of tablet processing. The popularity of wet granulation is because it can be applied to all drugs, and for many formulators it is the method of choice for drugs with a high dose and a very low dose. In this introduction we look at some of the main formulation factors that affect the properties of tablets made by wet granulation, and also touch on some process related factors concerning end point determination and scale-up. The process related factors are the source of a great number of studies and a comprehensive review is beyond the scope of this introduction, although it is possible to give general guidance concerning process related factors. The potential for various measurable factors to be used as end point detection has been extensively reviewed elsewhere.

Re-compaction properties of anhydrous lactose and mcc

The recommended starting ratio of SuperTab®21AN to Microcrystalline Cellulose for dry granulation is in the range 65:35 to 55:45. Pharmacel®102 Microcrystalline Cellulose (MCC) is beneficial to dry granulated formulations to reduce the compaction pressure needed to form hard tablets, but above a level of 35% to 45% reduction in tabletability of granules is observed.

Re-compaction properties of lactose and mcc

SuperTab®21AN (anhydrous lactose) is the preferred form of lactose for use in dry granulated formulations, because it does not suffer from reductionin tabletability after densification. Microcrystalline Cellulose (MCC) forms very strong compacts, despite the reduction in tabletability after densification.

Superdisintegrants Introduction to chemistry and performance

The superdisintegrants Primojel® (sodium starch glycolate) and Primellose® (croscarmellose sodium) are cross-linked and substituted polymers of glucose. The degree of cross-linking and substitution are important factors in determining the effectiveness of these materials as superdisintegrants. In the case of Primojel®, the selection of the type of starch is also a key factor, and in the case of Primellose®, particle size is important. This introduction to the chemistry and performance of superdisintegrants describes how the synthetic processes have been optimised to ensure peak performance of these two materials.

Use of lactose in hard gelatin capsules

SuperTab® 21AN, SuperTab® 30GR and sieved grades of Pharmatose® are all suitable for encapsulation in hard gelatin capsules based on their flowability (Carr’sIndex. SuperTab® 21AN gave the strongest plugs of all grades of lactose tested, and SuperTab® 30GR gave the strongest plugs of the grades of lactose monohydrate.

Roller compaction of anhydrous lactose and mcc

Blends of anhydrous lactose and Microcrystalline Cellulose (MCC) in the ratio 65/35 to 55/45 give granules with the optimal properties for roller compaction.Inclusion of MCC tends to decrease the roller compaction throughput rate and to increase the ribbon temperature during roller compaction. However, granule size and flow, and tablet weight uniformity are improved with the inclusion of Microcrystalline Cellulose (MCC). In this ratio, the loss of tabletability of MCC after roller compaction is minimal and inconsequential.

Wet granulation of milled lactose and mcc

Lactose is commonly wet granulation with microcrystalline cellulose in the preparation of pharmaceutical tablets. The studies reported in this article examine the effects of lactose / MCC ratio, lactose particle size and polyvinylpyrrolidone concentration on granule and tablet properties.

Particle size measurement of lactose for dry powder inhalers

The particle size of lactose has been shown to be important for dry powder inhalers (DPI). Therefore it is important to use robust techniques for the measurement of the particle size of lactose. In this paper, various aspects for the determination of the particle size of lactose for dry powder inhalers are discussed. For reliable results it is important to take representative samples and to have an exchange of the particle size method between supplier and user.

Lactose some basic properties

Lactose is the most important carbohydrate of the milk of most species. Its biosynthesis takes place in the mammary gland. Concentrations in milk vary strongly with species. Lactose is the first and only carbohydrate every newborn mammal (including human) consumes in significant amounts. Bovine milk contains 45 – 50 grams lactose per liter. Industrially lactose is produced from bovine milk exclusively, or rather from milk derivatives like cheese whey or ultra filtration permeate. Lactose is also known as milk sugar.

The influence of lactose particle size on DPI performance

In most dry powder inhalation (DPI) formulations carriers are used. Lactose is the most common used carrier. A DPI formulation could contain lactose for more than 99%. It is used as a flow aid and it facilitates the dose of the active into the lungs. The properties of lactose play an important role in the formulation of a dry powder inhaler and have extensively been investigated and described in the literature. The selection of lactose is based on the type of device, the filling process of the device and the final release of the active. The formulator for a DPI has various challenges. He should be able to get a homogeneous mixture where the drug particles adhere to the lactose. The adhesion should not be too strong as the drug will not be able to release from the lactose particle during inhalation. Furthermore, a low dose of powder should be filled into the device and the drug should always be released in the same way. One of the important parameters for the formulation is the particle size of the lactose. The role of the particle size of lactose in dry powder inhalers is discussed.

Use of Primojel® and Primellose® in wet granulation

Based on studies reported here, the inclusion of at least half of the disintegrant inside the granules is extremely important for formulations containing a high quantity of insoluble diluent. Use of all extragranular disintegrant in tablets based on dibasic calcium phosphate as the diluent gave tablets with unacceptably slow disintegration and dissolution.

Identifying safe use of pharmaceutical lactose

This leaflet describes lactose intolerance being caused by lower than normal levels of the enzyme lactase in the gut, which makes it difficult for some patients to digest lactose, causing discomfort and other unpleasant symptoms. Medical researchers have studied how lactose intolerant patients respond to different levels of lactose, and published studies at last provide some real clarity about safe levels of exposure.

Technical papers overview


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