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Download-articleNew tablet testing method predicted tableting failure at the commercial scale and will prove useful for scaling up production

 

Abstract

We previously determined “Tableting properties” by using a multi-functional single-punch tablet press (GTP-1). We plotted “Compactability” on the x-axis against “Manufacturability” on the y-axis to allow visual evaluation of “Tableting properties”. Here, we examined whether this evaluation method can be used in the formulation design of tablets prepared by wet granulation. We used the GTP-1 to measure “Tableting properties” with different amounts of binder, disintegrant, and lubricant, and compared the results with those of tableting on a commercial rotary tableting machine. Tableting failures (capping and binding in particular) occurred when samples that had been evaluated as having poor “Compactability” or “Manufacturability” on the GTP-1 were compressed on the rotary tableting machine. Thus, our evaluation method predicted tableting failure at the commercial scale. The method will prove useful for scaling up production.

This study was carried out using the Gamlen R series – formerly Gamlen Tablet Press (GT-1)

21 August 2017


Download-articleTaking the guesswork out of tablet manufacturing assessments

 

Most tablet formulations are developed and manufactured on a large scale without any objective assessment of their ability to form tablets, or whether they are adequately lubricated.

With the latest tablet presses measuring both of these parameters, as well as a third critical quality attribute (CQA) – punch sticking (or take-off ) force – taking measurements on small amounts of material may start to offer improved process understanding and control.

Main Methods 

The principal production methods for tablets are direct compression, dry granulation (DG) and wet granulation. The product control strategy (PCS) is based on understanding the links between the formula and process, CQAs and the certificate of a pharmaceutical product. Generating the data to support the PCS is therefore key to meeting the regulatory expectations of Quality by Design (QbD).

The development of the formulation and process is usually an iterative one, in which it is adjusted based on evaluation of intermediates and products. All of these are carefully evaluated to understand the impact of formulation and process changes on product quality, in addition to supporting QbD. The manufacturing scale used during formulation development largely depends on the amount of drug substance and the equipment available.

7 August 2017


Download-articleStructure and tablet properties of paracetamol granules prepared in fluidized bed and by wet massing

 

Summary

The structure of granules prepared by fluidized bed granulation and by wet massing, have been compared using a solvent extraction technique and scanning electron microscopy. The properties of tablets prepared from compression mixes of the granules have also been examined.

Small but significant differences were observed in both granules and tablets. The binder in both granule types was present as a sponge-like matrix, but the distribution of binder in the fluidized bed granules was less uniform than in the wet massed product.

The fluidized bed granules contained surface patches of binder and compressed to form tablets of improved tensile strength. The fluidized bed granules were more porous than the wet massed granules, and tablets prepared from the fluidized system had improved disintegration and dissolution characteristics.

23 June 2017


Download-articleGamlen Instruments company overview

 

We provide high performance instruments, support and training to help scientists create innovative products.

To create new and better products you need to carefully study and understand the relationship between drug properties, formulation and manufacturing process under properly controlled laboratory conditions.

Technical breakthrough uses ‘force control’ instead of ‘thickness control’ with minimal loss of materials

Until recently small scale tablet manufacture using ‘controlled compaction force’ had not been possible because of technical limitations based on thickness control and large scale production.

New breakthroughs by Gamlen Instruments mean scientists now have the ability to manufacture small batches of tablets and conduct advanced research and development using portable benchtop instruments.

16 June 2017


Download-articlePredicting effects of punch shapes on tableting failure using a multi-functional single-punch tablet press

 

Summary

We previously determined “Tableting properties” by using a multi-functional single-punch tablet press Gamlen R series (formerly GTP-1). We proposed plotting “Compactability” on the x-axis against “Manufacturability” on the y-axis to allow visual evaluation of “Tableting properties”. Various types of tableting failure occur in commercial drug production and are influenced by the amount of lubricant used and the shape of the punch.

We used the Gamlen R series (formerly GTP-1) to measure “Tableting properties” with different amounts of lubricant and compared the results with those of tableting on a commercial rotary tableting machine. Tablets compressed with a small amount of lubricant showed bad “Manufacturability,” leading to sticking of powder on punches. We also tested various punch shapes. The Gamlen R series (formerly GTP-1) correctly predicted the actual tableting results for all punch shapes. With punches that were more likely to cause tableting failure, our system predicted the effects of lubricant quantity in the tablet formulation and the occurrence of sticking in the rotary tableting machine.

6 June 2017


Download-articleAnalysis of PROSOLV® EASYtab with added Ascorbic Acid

 

Summary

The objective of this work was to establish the effect of adding a range of concentrations of ascorbic acid to PROSOLV® EASYtab, a multi-functional tableting excipient. The work was done using the Gamlen D series powder compaction analyser and included a wide range of key compression parameters. EASYtab was found to be an exceptional material with a large capacity for dilution; even material containing 40% ascorbic acid had excellent compaction characteristics.

25 May 2017


Download-articleHow to reduce the risk of tablet picking and sticking using the Gamlen D series

 

Summary

Poor lubrication results in picking and sticking problems during production. These are one of the most common causes of tablet defects which result in slow running of the tablet press and reduced output. High ejection stress (>5 MPa) is strongly correlated with manufacturing problems.

The effect of lubricant concentration on tabletability, tablet ejection and detachment can be evaluated using the Gamlen D series. Lubricant effectiveness rank order varies between materials; some materials are better lubricated by sodium stearyl fumarate than by magnesium stearate.

Detachment (take-off) force and peak ejection force should be evaluated as potential critical quality attribute for tablets.

16 May 2017


Download-articleFormulating minitabs – a study of SmartEx™ – a cellulose derivative

 

Summary

The study of the behaviour of the Orodispersant excipient was successful as a wide range of compaction forces yielded tablets of good tensile strength. Most of the tablets made disintegrated within the required 30 seconds duration except for those made using 2.5kN (250kg or 330MPa) force. This means that the excipient will positively influence solid dosage formulation.

20 April 2017


Download-articleUse of a manufacturability profile to simplify tablet formulation evaluation

 

Summary

Development of a manufacturability protocol for laboratory use is an important process of developing tablet formulations and managing tablet quality. The manufacturability protocol developed for use on a simple laboratory instrument can be used throughout the lifecycle of the product from research to manufacturing, and generates key data to ensure quality on an ongoing basis.

Introduction

To measure the properties of materials intended for compression requires a suitable instrument. In the past this has been done using an instrumented tablet press or a compaction simulator. We have developed a benchtop powder compaction analyser which enables the user to fully characterise a material quickly and easily and using a small amount of material to establish its Critical Quality Attributes on compaction.

18 April 2017


Download-articleEarly processability assessments during product development can help identify optimal API for efficient processing

 

Summary

Efficient downstream processing of active pharmaceutical ingredients (APIs) can depend strongly on their particulate properties, such as size and shape distributions. Especially in drug products with high API content, needle-like crystal habit of an API may show compromised flowability and tabletability, creating significant processability difficulties on a production scale.

However, such a habit can be adapted to the needs of downstream processing. To this end, we modified the needle-like crystal habit of the model API 5-aminosalicylic acid (5-ASA). This study reports processability assessment of six representative crystal habits of 5-ASA (needles, plates, rectangular bars, rhombohedrals, elongated hexagons, and spheroids) in the context of direct compression using ring shear tester, flow rate analyzer, and Gamlen D series.

As expected, needles were very cohesive, had low flow rate (1.0 ± 0.08 mg/s), and low bulk density (0.14 ± 0.01 g/mL) but showed better tabletability, whereas the opposite was observed with more isotropic crystal habits. For instance, spheroids, elongated hexagons, and rhombohedrals were easy/free-flowing and had high bulk densities (≥0.5 g/mL), but final tablets had lower tensile strength than that of needles. Of the six crystal habits, the plates showed a good compromise considering both flowability and tabletability.

24 March 2017


Download-articleUser group presentation – Gamlen Instruments presentation

 

Developing a fair test to understand compaction.
Tablet Quality is hard to measure.
You need to contol compaction FORCE.

22 February 2017


Download-articleUser group presentation – Imperial College London

 

Tablet dissolution study using the Gamlen R series

The overall aim of this study is to understand and gain an appreciation of the importance of tablet formulation and dosage form design in pharmaceutical product development.

22 February 2017


Download-articleUser group presentation – Jordanian Pharmaceutical Manufacturing Company

 

Understanding the Force Displacement Curve of Compacted API’s using the Kawakita Model of Compression

22 February 2017


Download-articleUser group presentation – Sawai Pharmaceuticals, Japan

 

Characterization of tableting properties measured with Gamlen R series for several pharmaceutical excipients and actual tablet formulations

22 February 2017


Download-articleUser group presentation – Shin-Etsu, Germany

 

Application studies using the Gamlen D series at an excipient manufacturer’s laboratory


Key purpose:

Formulation screening before transfer to rotary press – saving material.
Four studies include:

  1. Correlation of Gamlen D series and Romaco Kilian Pressima Rotary Press
  2. Application in formulation development (lubricant optimization)
  3. Analysis of SiO2 addition to excipient and testing tablet hardness
  4. Analysis of elastic recovery and ejection forces in L-HPC formulations

22 February 2017


Download-articleUser group presentation – University of Chemistry and Technology Prague

 

The development of secondary porous structure in compressed binary mixtures of particulate solids.

22 February 2017


Download-articleUser group presentation – University of Thessaloniki, Greece

 

Co-spray dried metformin hydrochloride with polymers for compaction improvement

Spray drying (SD)
One-step process – Applications
Product is made by co-spray drying solution

Two case studies:

  1.  API incorporated at levels less than ~60% aiming at a matrix formulation (molecular solution or particulate fine dispersion) for controlled release. (Van den Mooter et al. 2012. Drug Discovery Today: Technologies, 9, 79).
  2. API incorporated at usually high levels > 90% aiming at surface modification of drug particles and improved flow and compression (less explored)

22 February 2017


Download-articleWhat you didn’t know about breakage of anisotropic rod-shaped particles

 

Summary

Many products and intermediaries in industry are manufactured in the form of anisometric particles, depending on the molecular composition and finalization process (e.g. active pharmaceutical ingredients or pigments in dye industry). Some technological steps (filtration, filter washing, drying, transportation) can lead to uncontrolled changes in the Particle Size Distribution (PSD) due to particles attrition and breakage. When a randomly packed layer of anisometric particles is compressed (its weight, external force), it is of interest, both academic and practical, to find the relationship between the applied stress, compressibility and breakage.

In this experimental study, behaviour of dry granular layers of monodisperse cylindrical particles (8×1 mm) under uniaxial compression was studied. The layer compressibility and PSD were evaluated. The effect of several parameters was investigated: piston speed, layer size (diameter and height), applied pressure. Two modes of compression were tested: non-recurring and recurring. In the former mode, after the compression, the particles were taken out of the measuring cell for granulometry. In the latter mode, after granulometry, the particles returned to the cell for the next run with the same pressure.

It was found that neither the piston speed nor the layer size were relevant, within our experimental range. The resulting compressibility and PSD were affected mainly by the normal pressure and the way it was applied. In the non-recurring mode, with increasing pressure, PSD moves toward smaller sizes of broken particles always leaving some initial particles intact. In the recurring mode, the pressure had more destructive effect, resulting in larger particle fragmentation. The reason is seen in the particle re-arrangement between the successive tests.

31 January 2017


Download-articleCharacterization of tableting properties measured with a multi-functional compaction instrument for several pharmaceutical excipients and actual tablet formulations

 

Abstract

Before designing tablet formulations, it is important to understand the “Tableting Properties” of excipients and API (active pharmaceutical ingredient) powders. Those properties refer to “Compress-ibility”, “Compactability” and “Manufacturability”, which are difficult to evaluate quantitatively. In this study, we aimed to evaluate the “Tableting Properties” by using a benchtop single-punch tablet press, developed recently to measure these parameters using a single device. In order to facilitate understanding of the results visually, we proposed a new plot, where the X-axis showed the tensile fracture stress and the Y-axis showed the ejection stress. This plot, which is composed of four regions, shows the combination of “Compactability” and “Manufacturability”. We confirmed the ability of this device to evaluate the characteristics of typical pharmaceutical additives as a value of “Tableting Properties”. Losartan potassium was used as an API, and Dilactose R and MCC as an excipient with good “Tableting Properties”. The ejection stresses of losartan potassium and Dilactose R were very high. An increase in magnesium stearate shifted the point along the Y-axis in this plot, and it meant an improvement in “Manufacturability”. It was confirmed that the device and plot are useful in designing formulations efficiently using a small amount of sample powders. ã 2016 Elsevier B.V. All rights reserved.

9 December 2016


Download-articleAAPS posters – Comparison of the tensile fracture stress of ammonium sulfate crystals and tablets

 

14 November 2016


Download-articleAAPS posters – Can we predict hygroscopicity of a tablet from its starting materials?

 

14 November 2016


Download-articleAAPS posters – Effect of compaction speed and compaction dwell time on tabletability and compactibility using a dynamic powder compaction analyzer

 

14 November 2016


Download-articleAAPS posters – Evaluation of the properties of a model caffeine tablet formulation using a surface dissolution imaging system and a dynamic powder compaction analyzer

 

14 November 2016


Download-articleAAPS posters – Comparison of tablet ejection and detachment stresses using a dynamic powder compaction analyzer

 

14 November 2016


Download-articleAAPS posters – Development of a manufacturability protocol for use with a laboratory powder compaction analyzer

 

14 November 2016


Download-articleDevelopment of orodispersible minitablets with lorazepam using Gamlen R series (formerly Gamlen Tablet Press GTP-1)

Introduction

Lorazepam is commonly used for sedation in pediatric and neonatal intensive care units and in the treatment of status epilepticus. However, for children under 12 years of age, injection is the only available marketed preparation. In pharmaceutical practice compounded suspensions prepared from powdered lorazepam tablets are prescribed.

The aim of the study was to develop orodispersible minitablets (ODmT) with lorazepam as an acceptable and age-appropriate pediatric dosage form. They can be easily swallowed even by infants because of their small sizes and rapid disintegration in the mouth.

Besides, the properties of minitablets prepared with a single punch laboratory tableting machine and with rotary press were compared to demonstrate potential problems with product development.

28 September 2016


Download-articleAssessing tablet manufacturability: will your powder formulation actually produce a good tablet?

What is a good tablet?

To check if a powder will make a good tablet is a complex process because good tablets require qualities that can sometimes conflict with each other. For example, the powder needs to be well-lubricated but the tablet also needs to be easily penetrated by fluid in the gut. The tablet needs to be physically robust but also break down rapidly in the body. As is stated by Amidon et al (1):

“A critical process in manufacturing the tablet dosage form is that of powder compression. Although this process has been used routinely for over a century, problems persist related to powder compression in pharmaceutical formulation development and manufacturing. Common problems include tablet failures such as capping and lamination; powder sticking to punch surfaces or die wall; and insufficient mechanical strength to withstand stress in downstream processing. The properties of compressed tablets are sensitive to both material characteristics and process parameters.”

26 September 2016


Download-articleQuality matters

Recent FDA changes are likely to have a major impact on development costs and timelines within the generics industry. This will be difficult for smaller manufacturers in particular to implement, but looks set to enhance quality standards.

26 September 2016


Download-articleTablet manufacturability assessment

Determining whether a powder will form a good tablet is a complex process because for a material to make a good tablet it requires a number of different attributes which in some ways conflict with each other.

For example it needs to be well lubricated but also to be easily penetrated by fluid in the gut. It also needs to be physically robust but also break down rapidly in the body.

The parameters we have identified which determine manufacturability are set out below.

The most important requirements are for it to be readily compressible, well lubricated, and to exhibit acceptable recovery (as excessive elastic recovery has been associated with manufacturing defects such as capping.

8 June 2016


Download-articleTablet analysis – Tablet exam: using dynamic compaction analysis to ensure successful formulations

Article published by Tablets & Capsules May 2016

Authors: Joe Domingue, SciMark International
and Michael Gamlen, Gamlen Tableting

Scientists tasked with formulating and manufacturing robust yet effective tablets face many challenges.

These include:

Optimizing tablets during early stages of development when access to affordable and easy-to-use tools is limited

Identification of critical quality attributes (CQAs)

Characterization of the suitability and batch-to-batch tolerances of key excipients

Accessing API-excipient and excipient-excipient compatibilities

Determining critical process parameters

This article highlights a comprehensive tablet exam protocol that combines dynamic powder compactions analysis with tensile fracture stress measurement of the resulting tablet.

Together these measurements provide a fast, affordable and highly predictive measurement of the ultimate tabletablity of a pharmaceutical powder formulation.

They also provide unique real-time insights into the compaction process.

2 June 2016

 


Download-articleHow to achieve targeted delivery of the poorly soluble active ingredient dipyridamole

 

Introduction

The poor physicochemical properties of many drugs present challenges when targeting delivery to site-specific regions of the gastrointestinal tract for either a systemic or topical effect.

For poorly soluble basic drugs administered by the oral route, often delivery in a salt form is favoured since within the low pH environment of the stomach the drug is maintained in an ionised state, which often leads to significant improvements in aqueous solubility. However, post gastric emptying, upon transit into the proximal small intestine there is a rapid pH shift to more basic conditions, which can lead to uncontrolled precipitation of the neutral species of the drug. As the drug needs to in solution at the site of absorption, this precipitation can lead to varied or low bioavailabilities when dosed orally.

In order to overcome this challenge, drugs are often formulated in enteric dosage forms, however, typically they do not generally release drug into the small intestine until 1-2 hours post gastric emptying. As small intestinal transit is known to be relatively constant at 3-4 hours, this can greatly reduce the proportion of the dose available for systemic absorption, especially if drug absorption occurs in the proximal small intestine region1. Therefore, for basic drugs a formulation is often required whereby the drug is released directly at the site of absorption in a physical or chemical state that affords sufficient solubility/dissolution kinetics in the biological fluid media.

30 April 2015


Download-articleHow drug supplier compressibility evaluation can help make informed decisions

 

Using the Gamlen Tablet Press, this study generated unique information on less than 1g of each drug substance tested. This could not have been produced any other way. It enabled client to make informed decisions about suppliers and their suitability. These principles have widespread applications in many areas.

23 April 2015


Download-articleHow to improve tablet manufacturing process using rapid formulation assessments

 

Introduction

Tablet formulation and reformulation suffers from the issue that prior design is difficult based on present knowledge. A critical attribute of a formulation is not routinely tested – namely its compressibility. In this paper we present a systematic approach to tablet formulation development using a Gamlen Tablet Press capable of providing a compressibility assessment on milligram quantities of material. We evaluated a number of direct compression excipients as possible substitutes for an existing wet granulated formulation, maintaining as closely as possible the original qualitative formula. The change of the wet granulation manufacturing step to a direct compression process would not only save the manufacturer time and cost but also provide a simple regulatory change route if the excipients remain the same.

10 April 2015


Download-articleStudy results produced on Gamlen Tablet Press are scalable to high speed Fette production press

 

Comparison of 100mg of two particular formulations (obtained from a major pharma company) compacted on the Gamlen Tablet Press (GTP-1) showed matching results when compared with production data obtained on a high speed rotary tablet press (Fette 2090)

3 April 2015


Download-articleGamlen Tablet Press improves tablet development process

 

The hardness of a tablet has traditionally been used as a measure of quality; however, tensile strength is more appropriate when comparing tablets of different composition, shape and size, and compressed on different pieces of equipment.

The modern tablet is a complex drug delivery system where the drug substance is combined with a number of excipients to aid formulation of the desired product. These include bulking agents, binders, disintegrants and coatings all of which have some function to aid the processing of the drug substance into the end product form.

The excipients and drug substance are processed through a number of unit operations such as mixing, blending, granulation, tableting and often coating to form the final product.

30 March 2015


Download-articleHow to make the right decisions about drug suppliers and their suitability

 

A client asked us to evaluate two raw material suppliers in respect of compressibility and batch to batch variability. Samples of two batches of Supplier 1 material were compressed (without any processing or the addition of lubricant). Compressibility of the two batches was very similar in the pressure range up to 500MPa, which is the normal maximum used during tableting.

24 March 2015


Download-articleReducing risk in tablet development and manufacture

 

This article describes how measuring material properties that relate directly to the final tablet product, including the inherent ability of materials to form tablets (compressibility) reduces the overall risk in tablet development and manufacture. A case study illustrates the benefits of rapid compressibility assessment.

7 March 2015


Download-articleWhy you need to understand Critical Quality Attributes in order to optimise the manufacturing process

 

It is important that tablet properties such as tablet hardness be compared in a meaningful way when comparing formulations particularly when the tablets are compacted on different pieces of equipment. The properties of a tablet, both during manufacturing and in vivo, are determined by the properties of the materials used to make it; and the manufacturing conditions used to prepare the powder blend and compress the tablet.

6 February 201


Download-articleAccurate and reliable measurement of tablet detachment and ejection forces using Gamlen Tablet Press

The effect of lubricant concentration on tabletability, tablet ejection and detachment can be evaluated using the Gamlen Tablet Press. Lubricant effectiveness rank order varies between materials; some materials are better lubricated by sodium stearyl fumarate than by magnesium stearate.

Detachment (take-off) force and peak ejection force should be evaluated as potential critical quality attribute for tablets.

28 September 2015


Download-articleWhy material compressibility assessments are essential to tablet drug development and manufacture

Study demonstrates importance of material compressibility assessments in tablet drug development and manufacture.

Material compressibility (the inherent capability to tablet) influences drug substance properties such as adsorption, dissolution rate as well as hardness and friability.

Using a Gamlen Tablet Press, accurate measurement and data is provided, making the tableting process quick, robust and reliable.

23 September 2015


Download-articleHelping you maintain your leading edge in pharmaceutics teaching and research

The Gamlen Tablet Press – A major breakthrough in pharmaceutics teaching and research

  • The only instrumented laboratory tablet press suitable for student use
  • Simple to use with unique measurement capabilities
  • Measures all key parameters of the tablet compaction process
  • Suitable for undergraduate use and postgraduate research
  • New technology means that most data generated is suitable for publication
  • Integrated system for the study of tablets – used for tablet compaction AND tablet fracture

16 September 2015


Download-articleHow to formulate tablets on a small scale using the Gamlen Tablet Press

Characterisation of the compaction process is an important element of tablet development. Better understanding of tablet compression and ejection behaviour is essential for generation of data needed to support requirements of Quality by Design. It will help establish a more robust and reliable process, save time and money, and result in real patient benefits. We recommend widespread adoption in the industry.

9 September 2015


How to make better tablets using QbD and the Gamlen Tablet PressDownload-article

The solution to reliably identifying and solving many tableting problems lies in the nature of a conventional tablet press. Single punch and rotary tablet presses work on a similar principle which is to compress material to a particular thickness. This is determined by the upper punch position on a single punch tablet machine, and the distance between the upper and lower rollers on a rotary tablet machine. Very small differences in thickness, (even a few tenths of a millimetre), can have a dramatic effect on tablet properties.

26 August 2015


Download-articleInfluence of physicomechanical properties of starches on their tabletability – A multivariate analysis

Out of the six different grades of starches studied PURE-DENT® B830 and SPRESS® B818 showed better tabletability regardless of similar MC and amorphous nature. The better tabletability of these two starches might be attributed to their better plasticization due to loosely bound associated water, and low elastic recovery in the decompression phase.

7 July 2015


Download-articleWhat you need to know about tablet compression and the tablet manufacturing process

Tablet hardness has traditionally been used as a measure of quality, but tensile strength offers greater accuracy when comparing tablets of different composition, shape and size – and compressed on different equipment.

Learn how the Gamlen Tablet Press provides greater accuracy and more valuable data.

17 May 2015


Download-articleAPS poster – Effect of drug particle size on the compaction of dry granulated paracetamol tablets

Granulation is a method of size enlargement of small powder particles. Roller compaction (RC) is widely used in the dry granulation of powders, but the lack of availability of processes to evaluate small amounts of material using RC poses a serious limitation on early evaluation. Compaction simulators have been utilised to produce slugs with solid fractions that match the ribbons produced in RC1. Particle size, solid fraction, tabletability, compressibility and compactibility may be considered as Critical Quality Attributes of tablets and are key parameters in “Tableting by Design.”

This study investigated the effect of particle size and compaction pressure during dry granulation on the compressibility, compactibility and tabletability (see Fig. 1) of paracetamol tablets prepared from slugged granules. The Gamlen Tablet Press GTP-1 (Fig. 2) was used as a RC simulator for the dry granulation process, and for tablet compaction and tablet tensile fracture stress measurements.

12 September 2014


Download-articleTablets under pressure

The hardness of a tablet has traditionally been used as a measure of quality; however, tensile strength is more appropriate when comparing tablets of different composition, shape and size, and compressed on different pieces of equipment.

20 August 2014


Download-articleEffect of drug particle size on the compaction of dry granulated paracetamol tablets

 

Use of roller compaction (RC) is increasing within the pharmaceutical industry.Critical Quality Attributes (CQAs) for roller compacted materials include ribbon solid fraction, particle size, and compressibility of the final granules. Suggested optimal CQAs for roller compacted ribbons or dry granulated slugs seem to vary between authors. Zinchuk et al (1) used a compaction simulator to mimic the compression process of a roller compactor, and suggest that the optimal solid fraction range for the first compaction phase is from 65-80%. Farber et al (2) imply much higher solid fraction values and propose a Unified Theory of Compaction for roller compacted materials containing a high proportion of Avicel. Falzone et al (3) studied roller compaction of paracetamol using a chilsonator and hydraulic press, and the effect of broad range of product attributes. Data were analysed using statistical model but no recommendations for CQAs were made.

Small scale formulation of RC product s is difficult because of limited equipment availability and minimum batches sizes for processing. The Gamlen Tablet Press (GTP), an instrumented laboratory machine with punch position, compaction pressure, detachment force, and ejection force measurement capabilities which was used to make both the dry compacted slugs and the final tablet formulation. The GTP can handle small amounts of material and is being used for small scale formulation development. Pitt (4) has recently demonstrated that tablets produced using the laboratory system have very similar properties to those produced using a Fette 2090 production tablet in respect of compressibility, tabletability and ejection behaviour.

In this study the effect of drug substance grade and the solid fraction of the first compacted product on dry granulated paracetamol lubrication and compression was evaluated.

20 August 2014


Download-articleImportance of normalisation when comparing tablet properties

Tablet quality definition
The properties of a tablet, both during manufacturing and in vivo, are determined by the properties of the materials used to make it; and the manufacturing conditions used to prepare the powder blend and compress the tablet. Understanding the impact of starting material properties and manufacturing conditions on the tab let at the development stage is of paramount importance. Some material and tablet characteristics may not matter but others can have a dramatic effect on processing and in vivo behaviour. These physical and chemical properties are known as Critical Quality Attributes, and they must be established for starting materials, in-process materials, and the finished tablet.

18 August 2014


Download-articleTablet lubrication studies using the Gamlen Tablet Press

 

Lubricant optimisation is an important component of tablet formulation and process development. Many companies lack the capability to study lubrication on the laboratory scale. We have developed a new technique to measure both ejection and punch detachment forces using the Gamlen Tablet Press (GTP1). Ejection and punch take‐off force relationships were different between Galen IQ720 and Perlitol 500SD, also between magnesium stearate and sodium stearyl fumarate at 0.5 and 1.0% concentrations.

14 July 2014


Download-articleCharacterization of the compression properties of compacted chitosan as a function of molecular weight

Chitosan is a biodegradable polymer obtained by alkaline deacetylation of chitin. It is a linear copolymer of 2-acetamido-2-deoxy-D-glucopyranose and 2-amino-2- deoxy-D-glucopyranose joined by glycosidic bonds. Chitosan is nontoxic, biodegradable, biocompatible polymer having inherent film forming property which also exhibits biological activity. Chitosan is insoluble in water due to the rigid crystalline domains comprising its backbone structure. Depolymerization of the high molecular weight (MW) chitosan at a range of pHs produces a range of oligomers the MW of which depends on the extent of depolymerization. Bulk chitosan shows poor bulk density, flowability, die filling and compressibility. Roll compaction (RC) is widely used to increase the bulk density of low density materials. In this study the impact of RC on the compaction behaviour of chitosan was studied using a novel laboratory tablet press with full instrumentation.

7 July 2014


Download-articleCompression prediction accuracy from small scale compaction studies to production presses

 

Small scale compaction studies which utilise equipment representative of commercial scale tablet presses can be used to develop process understanding of pharmaceutical formulations using minimal quantities of material. In this study the scalability of compressibility (solid fraction vs. compaction pressure), tabletability (tensile strength vs. compaction pressure), compactibility (tensile strength vs. solid fraction) and ejection shear stress were examined over an eight-fold range in tablet size. Tablets of two representative commercially manufactured formulations were compressed and compared using a small scale compaction press and large scale industrial press. Different tablet sizes and shapes were produced from the two types of press. One formulation was manufactured by direction compression and the other by wet granulation. Generally good agreement was found across the scales for all the measures assessed. In addition, the measurement of ejection shear stress data on the small scale was able to accurately predict tablet failure on commercial rotary presses.

27 June 2014


Download-articleMiniaturised rotating disk intrinsic dissolution rate mearsurement; Effects of buffer capacity in comparisons to traditional wood’s apparatus

 

Purpose
The objective was to investigate the feasibility of using a miniaturized disk intrinsic dissolution rate (IDR) apparatus to determine the Biopharmaceutics Classification System (BCS) solubility class, and to develop an approach where IDR measurements performed in med ia of different buffer capacity could be compared.

Methods
The disk IDR values of 14 model drugs were determined at 37°C in US Pharmacopeia buffers at pH 1.2, 4.5, and 6.8. As little as 5 mg of drug were compressed in a die, with surface area of 0.071 cm2,with the die assembly rotated at 100 rpm in 10 ml media. Drug concentration was measured by an in situfiber optic ultraviolet method. The solubilities and pKa s were determined, and used to simulate dissolution profiles with a convective-diffusion-with-chemical-reaction model.

Results
The disk IDR values spanned six orders of magnitude (0.00014 to 114 mg min−1cm−2). The comparison of the miniaturized disk IDR values to published results using traditional dissolution bath apparatus indicated r2=0.99.

Conclusions
The results demonstrate that using 100-fold less drug does not sacrifice the quality of the measurement, and lends support to an earlier study Yuet al. (Int. J. Pharm. 270:221 – 227, 2004) that the disk IDR measurement may possibly serve as a surrogate for the BCS solubility classification.

7 June 2014


Download-articleMicrotablets

The poor physicochemical properties of many drugs present challenges when targeting delivery to site-specific regions of the gastrointestinal tract for either a systemic or topical effect.

For poorly soluble basic drugs administered by the oral route, often delivery in a salt form is favoured since within the low pH environment of the stomach the drug is maintained in an ionised state, which often leads to significant improvements in aqueous solubility. However, post gastric emptying, upon transit into the proximal small intestine there is a rapid pH shift to more basic conditions, which can lead to uncontrolled precipitation of the neutral species of the drug. As the drug needs to in solution at the site of absorption, this precipitation can lead to varied or low bioavailabilities when dosed orally.

In order to overcome this challenge, drugs are often formulated in enteric dosage forms, however, typically they do not generally release drug into the small intestine until 1-2 hours post gastric emptying. As small intestinal transit is known to be relatively constant at 3-4 hours, this can greatly reduce the proportion of the dose available for systemic absorption, especially if drug absorption occurs in the proximal small intestine region1. Therefore, for basic drugs a formulation is often required whereby the drug is released directly at the site of absorption in a physical or chemical state that affords sufficient solubility/dissolution kinetics in the biological fluid media.

18 May 2014


Download-articleFormulating tablets on a small scale

Quality by Design (QbD) is a new pharmaceutical development paradigm in which products are designed to take account the disease and its impact on the patient; the patient population; the drug properties; the preferred route of administration (from a clinical and a marketing perspective); and the requirements of the organisation manufacturing the product. In many cases the preferred dosage form will be an oral solid dosage form (OSD), usually tablets which are relatively cheap to manufacture and administer, and can be produced with a wide range of properties.

The basis of good science is the making of relevant and accurate measurements. This is particularly true in the case of tablet formulation developments. Tablets are complex products. Successful tablet development requires a good understanding of a number of key drug substance properties, as well as generating relevant and useful data on the formulation properties. Careful evaluation of the properties of the drug substance at the early stages is used to assist with the selection of both the salt of a new drug, and its polymorph form, as both of these can dramatically affect tablet properties and process selection.

12 May 2014


Download-articleImproved drug salt selection using an instrumented laboratory tablet press

Salt selection is an important part of the drug development process. Salts may be required for a variety of reasons including improving solubility, stability, or absorption properties. Improvements in processing cannot usually be considered at the early stages of development. The purpose of this study was to evaluate the possibility of checking salt compactions at an early stage of development using an instrumented laboratory tablet press and very small amounts of material.

4 May 2014


Download-articleMeasurement of tablet detachment and ejection forces using an instrumented laboratory tablet press

Successful implementation of the principles of Quality by Design relies upon the capability to make accurate and reliable measurements of material properties. The critical quality attributes (CQAs) relating to tablet compression are tabletability, compressibility and compactibility. The CQAs relating to tablet lubrication are the ejection profile (peak ejection force and ejection force vs displacement profile), and the punch detachment, or take-off, force (force required to detach the tablet from the punch). In principle these should be optimised on a product by product basis. Ejection studies on instrumented tablet machines are normally difficult to perform because the same load cell is used for measuring compression force as is used for ejection, but ejection forces are much smaller and so hard to measure accurately. Measurement of detachment, or punch take-off force is not normally undertaken at all during laboratory evaluation. The purpose of this work was to study the impact of blending time and lubricant concentration on ejection and detachment as a trial for QbD lubrication studies.

21 April 2014


Download-articleAn evaluation of various direct compression ingredients using the Gamlen Tablet Press GTP-1

The modern tablet needs to satisfy a number of parameters that make it fit for purpose such as hardness, potency, friability and dissolution as well as be suitable for commercial manufacture using a rotary tablet press. Performing a sufficient number of experiments to optimise the formulation is often limited by the quantity of API available and the nature of the equipment used. We present here an approach to tablet formulation using a novel bench top computer controlled tablet press—the Gamlen Tablet Press GTP-1. This requires only milligram quantities of material, is objective and practical. The approach is based on establishing the compressibility of the formulation as determined by tablet tensile strength measurements using the diametral compression test (Fell &Newton) over a range of compression pressures.

12 April 2014


Download-articleAn evaluation of various direct compression excipients using the GTP

Summary

Compressibility is a useful approach to screen formulations

  • GTP generates useful comparative data to help evaluate different grades of excipient and drug content
  • A ‘Decision matrix’ is a useful way of visualizing the data

29 March 2014


Download-articleEffect of repeated compaction of tablets on tablet properties and work of compaction using an instrumented laboratory tablet press

The repeated compaction of Avicel PH101, dicalcium phosphate dihydrate (DCP) powder, 50:50 DCP/Avicel PH101 and Starch 1500 was studied using an instrumented laboratory tablet press which measures upper punch force, punch displacement and ejection force and operates using a V-shaped compression profile. The measurement of work compaction was demonstrated, and the test materials were ranked in order of compaction behaviour Avicel PH101 > DCP/Avicel PH101 > Starch > DCP. The behaviour of the DCP/Avicel PH101 mixture was distinctly non-linear compared with the pure components. Repeated compaction and precompression had no effect on the tensile fracture strength of Avicel PH101 tablets, although small effects on friability and disintegration time were seen. Repeated compaction and precompression reduced the tensile strength and the increased disintegration time of the DCP tablets, but improved the strength and friability of Starch 1500 tablets. Based on the data reported, routine laboratory measurement of tablet work of compaction may have potential as a critical quality attribute of a powder blend for compression. The instrumented press was suitable for student use with minimal supervisor input

17 March 2014

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