Tablet processing: Formulation challenges and its solution

ABSTRACT:

Oral drug delivery is most commonly route of administration, when compared to all other route of administration. Oral route is most convenient, safe route of administration. Solid medicaments may be administered orally like tablets, capsules, pills, powders etc. One of the solid dosage form administered orally is tablet. One of the most critical steps in tablet is produce the tablets without any physical defect. This review provides a comprehensive report of problems. It is based on my personal experience and detailed study of several pharmaceuticals paper.

Keywords:

Oral drug, Oral route, Direct Compression (DC), tablets, Processing Problems.

 

INTRODUCTION:

Tablets are solid dosage form manufactured either by dry granulation, wet granulation or direct compression containing medicaments with or without excipients, intended to produce desired pharmacological response. Various types of tablets are being manufactured according the route of administration and type of dosage form. Tablets are the most frequent dosage form due to their advantages, for example, availability, easy administration, good stability, and low price. The easiest technology of production is still direct compression (DC)².

DISCUSSION:

 

TYPES OF TABLETS^5,6:

In broad sense tablets are classified as

1.    Compressed tablets⁸ 

2.    Molded tablets⁹.

These two tablet types are further classified base on purpose, use and mode of administration as

COMPRESSED TABLETS:

Oral tablets	Vaginal tablets
Chewable tablets	Sugar coated tablets
Buccal or sub-lingual tablets	Film coated tablets
Lozenges	Layered tablets
Effervescent tablets	Implants
Enteric coated tablets	Soluble tablets.
Sustained release tablets	Pressed coated tablets.

MOLDED TABLETS:

These are of two types as

1.      Hypodermic tablets

2.      Dispensing tablets

The main difference is compressed tablets are made on large scale while molded ones are made in very short scale for experimentation or for rare use.

FLOW CHART OF TABLETS¹:

Direct compression is more economic and straightforward in terms of good manufacturing practice requirements than are wet granulation and dry compaction, the pharmaceutical industry is focusing increasingly on this process. Although pharmaceutical industry is facing several problems which are either related to formulation or machine setting. In general, the tableting results are more important than the in-process (mixing) results because the tablet is the final product. An ideal tablet should be free from any visual defect or function defect. 

Typically, tableting problems only occur during scale-up and when using high-speed production-scale machines.As on date the tablet punching machines are well mechanized, the mechanical feeding of feed from the hopper into the die, electronic monitoring of the press, but tablet process problem still persists.

TYPES OF PROCESSING PROBLEMS AND ITS SOLUTION

An ideal tablet should be free from any visual defect or function defect. Problems such as tablet defects can cause     the company loss of production time and sales, and therefore money. Common problems that afflict the tableting industry include: 

1.      Black spot

2.      Weight Variation

3.      Hardness Variation

4.      Variations in the API dose

5.      Visual Defect

A.    Capping

B.     Lamination

C.     Sticking

D.    Picking

E.     Binding

F.      Cracking

G.    Chipping

H.    Double Impression 

1. BLACK SPOT: 

    There are number of possible reasons which are either related to formulation or with machine setting for  black spots in the tablet during compression. Some of these include

·     If formulation contains Calcium Phosphate (DCP/TCP) then there are chances of appearance of black particles during compression due to its abrasive nature.   

·        The incoming raw material basically talc, magnesium stearate and starch is another source, should be free from black particles. Before addition these are carefully sieved through different size meshes and inspected thoroughly. 

·    Spray-dried lactose is widely used as binder, filler-binder, and flow aid in direct compression tableting. It also causes the Darkening of the tablets on aging. The browning or darkening effect is considered to be due to the presence of large amount of contaminants (mainly 5-hydroxy furfural) which was not removed from the mother liquid before spray-drying. Lactose should be used limited and carefully. 

·     Continues high-speed operation increase the temperature and trapped the particles may charred  and appear on tablet.

 ·    Too much fines in the product which enters in between feed frame and turret and causes friction and produces black spots. 

·       Due to melting of drug (If drug have low melting) due to energy generation during compression. 

·        Improper setting of feed frame. 

      Overall, above said reasons might be need to check all mechanical operations involved along with lubricant used in machinery and for material. 

2. WEIGHT VARIATIONS^3,4:

 ·   One of the reasons of weight variation is lubricant or glidant less or not mixed evenly.To solve tablet weight variation, you also can add excipient aerosil or colloidal silicon dioxide. This excipient was added to the external phase. The amount used is usually 1-2% of the total weight of the tablet. Mixing for 10-15 minutes. If you need to add lubricant (Magnesium Stearate) as much as 0.5% -1%. But, keep in mind lubricant is hydrophobic, may interfere with dissolution of tablets.  

·      Secondly each tablet press doses a certain amount of powder into the die and this powder is then pressed into tablets by the upper and lower punch. This means that a volume is dosed, but the quality requirement is the weight. Hence, weight variations in a limited extent are quite normal due to variations in the density of the powder material and to a partially incomplete filling of the dies. The pharmacopoeias specify the acceptable level of weight variations. It must therefore be aimed at tableting a powder that can be dosed quickly and consistently in the dies. For this reason, very good flow characteristics are extremely important. 

3. HARDNESS VARIATIONS⁵: 

·   Weight Control. Maintaining the weight of the tablet is the key to controlling its hardness, fluctuations in the weight cause changes in the hardness of the tablet. Accuracy in the control of tablet weight with respect to a target weight is therefore especially important. A tablet that is lighter than the target tends to be soft tablet whereas a heavier tablet tends to be harder. If there are variations in the bulk density, then the die filling will not be consistent, resulting in wide variations in tablet weight. For this, very good flowable powder with homogeneity of the blend is very important. 

·        Scraper blade and die fill. The scraper blade is often overlooked as a item that wears, and should be replaced regularly. If the product is very abrasive, it may be that the scraper blade should be changed on a daily basis. For other regular products, the blade may last for several months. Blade lifetime is therefore dependent on the product type and how well the blade is maintained. 

4. VARIATIONS IN THE API DOSE^3,4: 

     Content uniformity is an important quality measure of the final solid dosage product. It ensures that a consistent dose of the API is maintained between batches so that the patient receives the correct dose. The active ingredient needs to be evenly distributed throughout the tablet to ensure that if the tablet is split in half, each half of the tablet has an equal dose The intention is to make sure that oral solid dosage (OSDs) do not have an abnormally low or high amount of API, which may arise because powder is blended and processed before being tableted or encapsulated. Non-homogeneity of the blend will lead to inconsistent dosage in the final product and could lead to product rejection, which will result in significant financial losses. Re-blending of a non-homogenous product is generally unfeasible, and the product needs to be scrapped.

    The major processing variables are mixing time, speed of mixing, and powder fill volume. Each of these parameters will, individually, have an effect on the blending efficiency. 

    The speed of mixing (or speed of rotation) will affect the quality of the blend. For free-flowing materials, the speed can be quite high and the materials will efficiently mix. However, for cohesive materials, the speed needs to be considerably slower to allow the ingredients to mix well. It is also important to determine the optimum powder fill volume within the blender. 

5. VISUAL DEFECTS⁷: 

    The most pharmaceutical tablets are not produced at the press’s maximum compression speed because it is not possible to produce tablets of acceptable quality at high rotation speeds. Defects such as capping, sticking and lamination etc occur, and the tablets become subject to weight and content variations. 

A. CAPPING 

     The upper or lower segment of the tablet separates horizontally, either partially or completely  from the main body and comes off as a cap, during ejection from the tablet press, or during subsequent handling. 

B. LAMINATION 

       Lamination is the separation of a tablet into two or more distinct horizontal layers. 

C. STICKING 

     Sticking refers to the tablet material adhering to the die wall. Filming is a slow form of sticking and is largely due to excess moisture in the granulation. 

D. PICKING  

    Picking is a more specific term that describes product sticking only within the letters, logos, or designs on the punch faces.

E. BINDING 

       Sticking of the tablet to the die and does not eject properly out of the die. 

F. CRACKING 

      Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as Cracks. 

G. CHIPPING 

    Chipping is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations. 

    There are number of possible reasons which are either related to formulation or with machine setting for above mention visual defect in the tablet during compression. Some important is as follows: 

Formulation related:

Large amount of fine powder.

Insufficient amount of binder or improper binder.

Insufficient or improper lubricant..

Granules/Powder not dried properly.

Too much binding causes chipping at bottom. 

Machine related: 

Incorrect adjustment of sweep-off blade.

High turret speed.

Poorly finished dies.

Rough punch faces.

    Majority of visual defect are due to inadequate fines or inadequate moisture in the granules or powders ready for compression or due to faulty machine setting. 

    Avoid the fine powder, increasing the amount of binder or adding dry binder and increase the amount of lubricant or change the type of lubricant. Dry the granules/powder properly. 

     Adjust sweep-off blade correctly to facilitate proper ejection, reduce speed of turret (Increase dwell time), Polish dies properly, investigate other steels or other materials and Increase pressure to optimum. 

H. DOUBLE IMPRESSION⁷:

      It is due to free rotation of punches which have some engraving or monogram on the punch faces. During his free travel, the punch rotates and at this point, the punch may make a new impression on the bottom of the tablet, resulting in 'Double Impression. 

     Use keying in tooling, i.e. inset a key alongside of the punch, so that it fits the punch and prevents punch rotation Newer presses have anti-turning devices, which prevent punch rotation. 

CONCLUSION²:  

   Tablets remain popular as a dosage form, due to the various advantages afforded both to the manufacturer and to the patient. Although the basic mechanical approach for most tablet manufacture has remained the same, efforts are continuously made to understand more clearly the physical characteristics of powder compaction and the factors affecting the availability of the drug substance from the dosage form after oral administration. Flow and homogenous blending of powder of a tablet directly relates to pharmacokinetics as disintegration time, dissolution time, absorption process, distribution, and elimination. Mixed the powder properly with considered physical characteristics, maintain adequate time, select the suitable mixer  and it must be validated considering the finished product performance. Example, Testing tablet hardness is ensuring the mechanical integrity of produced tablets during subsequent processes. There is no such official specification is given in any pharmacopoeia about the hardness of the material and hardness test. Formulator should have to decide and maintain the range of hardness during preparation based upon requirement and type of the formulation. Suppose hardness is very low about 18 to 20N and tablets pass the friability test and during packaging it creates no problem; then you can go ahead. Finally, selecting a granules or powder for compression requires a systematic approach with careful consideration of the performance of product, process, and machines. If powder flow is good, it will go uniformly into a die cavity and machines run with higher RPM and eliminate tablet rejection and it will increase productivity with quality.

 ACKNOWLEDGEMENT: 

    The authors are grateful to Mr. Gaurav Tripathi, Works Manager and Ms. Monika Tomar, Manager R&D ,Sigachi Industries Private Limited, Telangana, India  for support.

 REFERENCES: 

1.     Tablet compression – Photo courtesy: Research Gate.

2.  Ajay Kumar Singh “Impurities in pharmaceutical products How, Why, Characterize and Acceptance criteria in pharmasolution1.blogspot.com. 

3      USP, USP43-NF38 General Chapter <905> Uniformity of Dosage Units. 

4.    ISPE, “ISPE Group Working on Blend and Content Uniformity Launches Website,” Press Release, Sep. 16, 2014. 

5.      USP, USP43-NF38 <1151> Pharmaceutical Dosage forms-Tablets.

6.     The new USP general Chapter <1062> Tablet Compression Characterization has been approved and published in USP40-NF35, second supplement, June 1, 2017. The chapter will become official on December 1, 2017.

7.     Matthew Knopp “Resolving Tablets Defects”.

8.     Ajay Kumar Singh “Effect of Aqua- Organic medium on lon-dipole type Reactions” in ARJP.

9.    Ajay Kumar Singh “A study of alkaline Hydrolysis of ethyl isonicotinate” in ARJP.

 Abbreviations: 

     API: Active pharmaceutical ingredient, USP: United state pharmacopeia, NF: National formulatory, RPM: Rotation per minute, ,DC: Direct compression,OSD:Oral solid dosage DCP: Di calcium phosphate, TCP:Tri calcium phosphate. 

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