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Home Solid Formulation Strategies Tablet Manufacturing Technologies for Solid Drug Formulation

Tablet Manufacturing Technologies for Solid Drug Formulation

OVERVIEW OF COMMON TABLET MANUFACTURING TECHNOLOGIES
Compressed tablets typically consist of the active pharmaceutical ingredient (API) along with a range of excipients fulfilling various functions as
fillers, binders, disintegrants, lubricants, glidants, colorants and taste modifiers. In many cases, the compressed tablet is coated which requires
adding excipients such as a coating polymer, plasticizers, and pigments to the final list of formulation ingredients.

Despite being one of the most widely used oral solid dosage forms, formulating compressed tablets can be challenging. A critical first step is
selecting a suitable manufacturing approach and the right excipients for the formulation from a range of options that can support the desired
therapeutic effect by optimizing the release kinetics, stability, and API solubility.

TECHNIQUES FOR TABLET MANUFACTURING

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Among the most common techniques for tablet manufacturing are direct compression, dry granulation, and wet granulation.

Read more about

Direct Compression for Tablet Manufacturing

Granulation for Tablet Manufacturing
Formulation Workflow
Dry Granulation
Wet Granulation
Continuous Manufacturing
Advantages of Mannitol in Tableting Processes
 Direct Compression for Tablet Manufacturing

Direct compression (DC) is a highly efficient method for producing tablets. The process is straightforward and consists of blending the API and
excipients followed by compression. Unlike other common solid formulation approaches, DC contributes to sustainability efforts as it does not
require additional processing steps, does not require solvent and uses less energy in comparison to a process that uses granulation and tableting.
It is also well-suited for moisture- or heat-sensitive ingredients, when wet granulation (described below) cannot be used.

Low- and high-dose APIs can present a challenge for DC in different ways. With low-dose APIs, it may be difficult to achieve the necessary
homogeneity and uniformity as segregation, de-mixing, or sedimentation of the API may occur, especially if particle sizes of the formulation
components are quite different.

APIs often show poor galenical properties such as sticking, poor flow, and poor compressibility. Poor flow and compressibility, common with
small particle sizes or micronized APIs, can be compensated for with use of a suitable filler excipient, which would make up a relatively larger
portion of a low-dose API formulation. In high dose formulations, where the API content can range from 50% to nearly 100%, fillers often can’t
compensate for poor API properties. In such cases, typically dry or wet granulation methods are used as the resulting granules have improved
properties compared to the API powder.

Excipients with good flowability and compressibility can be used to address these challenges and ensure robust processability via DC. Specific
DC grades of excipients that meet these requirements are often available. It is important to note that the particle size distribution of excipients is
crucial for a stable mixture. For many excipients, there are different grades available with different particle sizes to meet different needs. For
example, excipients with very high surface areas can help stabilize a mixture by adsorbing micronized APIs on their surface.

Granulation for Tablet Manufacturing

Different options for tableting should be considered as each method has its own advantages and disadvantages and the selected approach will
have important process and business consequences.

While DC should always be considered for tableting as it is a highly efficient and straightforward approach, and many excipients are designed to
address challenges that may arise in DC processes, there are cases in which use of DC is not feasible. In these situations, granulation can be used
as an additional process step prior to tableting.

The granulation process enables particle enlargement by agglomeration. It eliminates undesirable powder characteristics and delivers the
properties required for subsequent process steps by improving content uniformity, flowability and compressibility. Granulation is, however,
more time-consuming than DC, and there is a risk of product cross-contamination and product loss during the granulation, drying, and sieving
steps. These factors can also contribute to a higher cost compared to DC.

Differences between wet and dry granulation processes are shown in the formulation workflow and benefits and drawbacks of the respective
approaches in comparison to DC are summarized in Table 1.

Formulation Workflow:

Dry Granulation: Does not require liquid/binders; no change of chemical composition

Slugging
Typically uses a tableting machine or rotary press to form “slugs”
Slugs are broken by e.g. a hammer mill to form granules
High-pressure method
Roller Compaction
Compression between two rotating rollers into plates or sheets
Plates are milled into granules
Gentler than slugging
Wet Granulation: needs binders; change of chemical composition

Table 1: Benefits and drawbacks of common granulation techniques used in solid oral dose manufacturing in comparison to direct compression.
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Direct compression Dry granulation Wet granulation

Short
Tableting of the powder blend Mechanical compression of Granulation of the powder
description
without any prior granulation powder material to form material using a binder.
step. granules.
 Decision basis
API sensitive to elevated API sensitive to elevated API sensitive to elevated
temperatures and/or moisture: temperatures and/or moisture: temperatures and/or moisture:
yes yes no
Suitable powder blend: through Suitable powder blend through Suitable powder blend through
excipient selection: yes excipient selection: yes excipient selection: no
Appropriate compressibility Appropriate compressibility Raw material variations: yes
Good flowability Raw material variations: yes (limited impact)
Stable homogeneity (no (limited impact)
demixing)
Raw material variations: no (high
impact)

Pros
Continuous manufacturing (CM) CM suitable Strong binding performance
suitable Solvent-free improving compressibility
Highly efficient process Broad application range
Reduced strain on API, making it Variety of approaches exist, such
highly suitable for sensitive APIs as high shear (HS), twin screw
Less time- and resource-intensive (TS) and fluid bed (FB)
Reduced number of process steps granulation, with HS and FB
Solvent-free being widely established
processes in large scale solid dose
manufacturing
CM suitable (TS, FB)

Cons
DC grades of excipients DC grades of excipients Organic solvents (FB)
potentially needed to ensure potentially needed to ensure High equipment footprint and
sufficient compressibility of the sufficient compactibility of the operating costs, e.g. due to
powder blend, can come with powder blend, can come with mandatory drying step
higher raw material prices higher raw material prices Residual solvent risk
Finding balance between robust
granules and remaining
compressibility potentially
challenging
Dedicated equipment needed

Dry Granulation
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 Dry granulation (DG) incorporates mechanical compression either by slugging or roller compaction while wet granulation (WG) uses a liquid and
typically a binder to facilitate agglomeration of the powder particles.

Forming granules without liquid using the DG technique requires compacting the mix followed by size reduction of the compacts to the desired
particle size.

DG can be used to improve flow properties and prevent segregation of components in cases where DC processes reach their limits, and to avoid
API degradation induced by WG. Because it does not use moisture, DG is especially well-suited for APIs that are sensitive to solvents or
moisture. Compared to wet granulation, DG is a shorter, more cost-effective manufacturing process.

As outlined in Figure 1, DG can be performed in two ways – slugging or roller compaction. With slugging, tableting presses are used to form large
tablets (slugs) which are then broken by a hammer mill to form granules. In roller compaction, the raw material is compressed into plates or
sheets between two rotating rollers, which are then milled into granules. Compared to slugging, roller compaction is very gentle, making it the
preferred approach with heat- and moisture-sensitive materials.

Another benefit of using a roller compactor is that the auger-feed system delivers the powder materials consistently between the two rollers. In
contrast, poor flow properties of the material may result in various degrees of densification of the compacts produced using table press
compaction.

Wet Granulation
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In WG, a liquid and typically a binder is used to granulate the powder and the process requires blending, wetting, wet mass stage, drying, and
sizing. The binder is typically a polymer such as polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), copovidone, starch or cellulose derivatives
dissolved in either an aqueous or organic solvent.

While aqueous solutions are eco-friendly and relatively less expensive than organic solvents, they can have a longer drying time. Examples of
organic solvents used in WG are ethanol and propanol.

Several approaches to WG are available:

High-shear processes use equipment that mixes the powder and liquid using high shear forces, accelerating the manufacturing process.
 Twin-screw granulation continuously manufactures wet granulate powders at lower liquid concentrations and with improved product
consistency.
Fluid bed granulation is a multiple-step WG process in which the powders are pre-heated, granulated, and dried in the same vessel. This
technique allows close control of the granulation process.

Success of the WG process depends on selection of appropriate excipients and choice of suitable process parameters which lead to the desired
binding and compaction properties and flow. As noted above, among the most widely used binders are PVA, PVP, copovidone, starch, and
cellulose derivatives; commonly used fillers in oral dosage forms include lactose, microcrystalline cellulose (MCC), calcium phosphates, and
mannitol.

Continuous Manufacturing

All of these tableting technologies can be either applied in traditional, stepwise, batch manufacturing or as part of a continuous manufacturing
process.

With continuous processes, it is important that the individual components show good flowability to ensure consistent and support a precise feed
and throughput which, in turn, ensures a consistent quality and performance of the final product. Also, in-process control is critical for
continuous processes and implementation of process analytical technology is key (in comparison to batch processes, where the final product is
tested and released for each batch).

Overall, continuous manufacturing offers several advantages compared to batch manufacturing including:

Improved efficiency with a single, end-to-end process operating in one location

Elimination of the need for scale-up to larger equipment
Greater consistency in final product quality
Reduced risk of human error with the use of in-process controls
Greater flexibility as production speed controls output
Reduced manual handling and less time needed for equipment cleaning

Advantages of Mannitol in Tableting Processes

When used as a filler in DC, WG, and DG, mannitol offers important advantages including low hygroscopicity chemical inertness, compactibility,
and the ability to form extremely robust tablets. A pleasant taste and mouth feel enables use for chewable, sublingual, and orodispersible tablet
formulations. In addition, mannitol is also suitable for use in continuous manufacturing; certain grades such as Parteck® M mannitol are highly
suitable for such processes due to their excellent flowability, compressibility and effect on blend uniformity for low dose formulations.

Learn more about formulation development and guidelines for these manufacturing processes and suitable excipients in our Formulation
Handbook.

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