Review Article

May - June 2018  |  Vol: 4  |  Issue: 3
In Process Quality Control Tests for Solid Dosage Forms: A Review

Sagar Kishor Savale*

Department of Technical Services, Mylan laboratories ltd, F-4 & F-12, Malegaon MIDC, Sinnar, Nashik, Maharashtra 422113, India

* Corresponding author,

Mr. Sagar Kishor Savale,

Department of Technical Services,

Mylan laboratories ltd, F-4 & F-12,

Malegaon MIDC, Sinnar, Nashik,

Maharashtra 422113, India.

Mobile No: 9960885333,

Email ID: avengersagar16@gmail.com

 

ABSTRACT

Objective: In-process quality control (IPQC) tests was done with a view to remove error from every stage in production and maintain the quality of the final product (FP) with standards as specified in the pharmacopoeias. Method: The quality of FP depends on in-process control (IPC) tests because it helps to incorporate excellence within the products. The quantitative and qualitative parameters of pharmaceuticals products was checked by finished product quality controls (FPQC) tests. The aim of this investigation was to provide concise information on the IPQC and FPQC tests for pharmaceutical solid dosage as per different pharmacopoeias. Conclusion: In the present investigation we was analyzed the quality control tests for tablets, capsules and other solid dosage forms.

Keywords: IPQC, Tablet, QC, IPC, RM, FP, Solid drugs, FPQC.


 

Introduction

In-Process Quality Control Tests(IPQC)was concerned with providing accurate, specific, and definite descriptions of the procedures to be employed, from, the receipt of raw materials (RM) to the release of the finished dosage (FD) forms(Figure 1).IPQC tests was performed in production area. Manufacturing practices was include in good quality finished products (FP) and had adequate considerations for safety of the employees is recognized as Good manufacturing practices (GMP).GMP is under with both production and quality control (QC).

                    

 

 

 

 

 

They should not carry any risk for the quality of product. In process testing enables easier identification of problems. It sometime identifies a defective product batch that can be corrected by rework, whereas once that batch has been completed, this may not be possible. Failure to meet in process control specification indicates either that procedure were not followed or some factor(S) out of control.

Instrument used in IPQC department

Number of Instruments which are used in IPQC test such as, Disintegration apparatus, Dissolution apparatus, Analytical balance Muffle furnace, Friability testing apparatus, Bulk density apparatus, Tablet hardness tester, Infra-red moisture content measuring apparatus, U.V Spectroscopy, Abbe Refractometer, T.L.C. kit and Karl fisher Titrimeter.

Official and Unofficial Tests for Evaluation of Tablets

1. Official Tests: Weight variation, Disintegration, Dissolution and Drug content.

2. Non-Official Tests: Hardness and Friability.

1. Official Tests

 

 

 

 

 

 

 

Figure 1: In-process Quality Control Test

1.1. Weight Variation Test(uniformity of weight)

Weigh 20 tablet selected at random, each one individually. X1, X2, X3… Xz

Determine the average weight X= (X1+X2 +X3+…+ Xz)/20.

Formula: Average Weight of Tablet – Individual Weight of Tablet / Average Weight of Tablet * 100.

Limit:

Upper limit = average weight + (average weight * % error), Lower limit = average weight - (average weight * % error), The individual weights are compared with the upper and lower limits, Not more than two of the tablets differ from the average weight by more than the % error listed, and no tablet differs by more than double that percentage.

USP XX-NF STANDARDS and IP STANDARDS of Weight variation test was reported in Table 1 and Table 2.

 

Table 1: USP XX-NF STANDARDS

Sr. no

Average wt. of tablet(mg)

Max. % difference allowed

1

130 or Less

10%

2

130-324

7.5%

3

More than 324

5%

 

           

Table 2: IP STANDARDS

Sr. no.

Average wt. of tablet(mg)

Max. % difference allowed

1

84  or Less

10%

2

84-250

7.5%

3

More than 250

5%

 

 

 

1.2. Content Uniformity Test

Randomly select 30 tablets. 10 of these assayed individually. The Tablet pass the test if 9 of the 10 tablets must contain not less than 85 % and not more than 115 %of the labeled drug content and the 10th tablet may not contain less than 75 % and more than125 % of the labeled content. If these conditions are not met, remaining 20 tablet assayed individually and none may fall outside of the 85 to 115 % range.

1.3. Disintegration Test (U.S.P.)

It is the time required for the tablet to break into particles, the disintegration test is a measure only of the time required under a given set of conditions for a group of tablets to disintegrate into particles. It is performed to identify the disintegration of tablet in particular time period. Disintegration test is not performed for controlled & sustained release tablets. According to the test the tablet must disintegrate and all particles must pass through the 10 mesh screen in the time specified. If any residue remains, it must have a soft mass. Disintegration test was performed in disintegration test apparatus (Figure2

 

).

http://t0.gstatic.com/images?q=tbn:ANd9GcTINhuwYXEGaLwpUktJXdcwv7tUi-0014saBsMu7fkeCrFCCRT-N3XGOMdX Figure 2: Disintegration Test Apparatus

 

 

1.3.1. Disintegration Media

Disintegrations test was conducted in different disintegration Medias such as, Water, Simulated gastric fluid (pH = 1.2 HCl), or Simulated intestinal fluid (pH = 7.5, KH2PO4 (phosphate buffer) + pancreatic enzyme + NaOH). Disintegration Testing Conditions and Interpretation was reported In Table 3.

 

 

Table 3: Disintegration Testing Conditions and Interpretation

Type of tablets

Medium

Temperature

Limit

Compressed uncoated

-

37 ± 20C

15 minutes or as per individual monograph

Sugar coated

If 1 or 2 tablets fail

Water

0.1 N HCL

37 ± 20C

60 minutes or as per individual monograph

Film coated

water

37 ± 20C

30 minutes or as per individual monograph

Enteric coated

0.1 N HCL &

Phosphate buffer pH 6.8

37 ± 20C

1 hr or as per individual monograph

Dispersible/ Effervescent

water

37 ± 20C

LST < 3 minutes or as per individual monograph

Buccal

-

37 ± 20C

4 hr or as per individual monograph

 

 

1.3.2. Disintegration Test for Uncoated, Coated and Enteric Coated Tablets

A) U.S.P. method for uncoated tablets: Start the disintegration test on 6 tablets. If one or two tablets from the 6 tablets fail disintegrate completely within 30min repeat the same test on another 12 tablet. (i.e. the whole test will consume 18 tablets). Not less than 16 tablets disintegrate completely within the time. If more than two tablets (from the 18) fail to disintegrate, the batch must be rejected.

B) For Coated tablets: To remove or dissolve the coat, immerse the tablet in distilled water for 5min.put the tablet in the apparatus in water or HCL for 30 min at 37oC (according to the U.S.P). If not disintegrated, put in intestinal fluid. If one or two tablets fail to disintegrate, repeat on 12 tablets. So 16 tablets from the 18 must completely disintegrate within the time, if two or more not disintegrated the batch is rejected.

C)U.S.P. and B.P Method for Enteric coated tablets: Put in distilled water for five minutes to dissolve the coat. Then put in simulated gastric fluid (0.1M HCL) for one hour. Then put in simulated intestinal fluid for two hours. If one or two tablets fail to disintegrate, repeat this test on another 12 tablets. So 16 tablets from 18 should completely disintegrate. If more than two fail to disintegrate the Batch must be rejected.

1.4. Dissolution Test

Dissolution is performed to check the percentage release from the dosage forms. i.e. Tablet.

Tablet breaks down into small particles which offers a greater surface area to the dissolving media. Disintegration test does not give assurance that particles will release drug in solution at an appropriate rate, that’s why dissolution tests & its specifications developed for all tablet products. Dissolution is mass transfer process. Dissolution is mainly depend on aqueous solubility of drug. It is process in which solid mass transfer in liquid medium. Dissolution based on four process such as, 1. Wetting 2. Solubility 3. Swelling 4. Diffusion.Particle size, shape, surface area is important factor can affect the rate of dissolution of drug. The aqueous solubility is increases, increases rate of dissolution drug. Dissolution test was performed in dissolution test apparatus (Figure 3).

 

 

        

Figure 3: Dissolution Test Apparatus

 

1.4.1. Various terminologies related to dissolution test

A) Dissolution: solid mass transfer process in to liquid medium. B) Diffusion: diffusion is mass transfer process of individual molecules of atoms having continuous random molecular motion contain in concentration gradient is known has Diffusion. C) Dialysis: separation of easily diffusible particle from poorly diffusible particle through semipermeable Membrane. D) Ultrafiltration: separation of colloidal particle from sub colloidal particle through semipermeable membrane. E) Osmosis: The passage of solvent molecule into solution through semipermeable membrane. F) Semipermeable membrane: Thin layer that can separate two phases. G) Steady sate: Mass transfer process is remains constant per unit time. H) Osmotic pressure: The pressure is exerted in walls of semipermeable membrane through concentration gradient. I) Diffusant (penetrant): the amount of material transport in semipermeable membrane. J) Con. Gradient: concentration of material transport in region of high con. To region of low con.

1.4.2. Mechanism of Dissolution

Dissolution mechanism based on two concept one is a mass transfer process. Second is the concentration of receptor compartment is maintain lower level as compared to donor compartment is known as sink condition.

1.4.3. Theories of Drug Dissolution

Dissolution concept mainly deepens on dissolution theories. There are three theories such as, Diffusion layer model/Film Theory, Danckwert’s model/Penetration or surface renewal Theory and Interfacial barrier model/Double barrier or Limited solvation theory.

1.4.4. Factor Affecting Dissolution

Drug Dissolution rate was affected by various factors such as, Physicochemical Properties of Drug, Drug Product Formulation Factors, Processing Factors, Factors Relating Dissolution Apparatus and Factors Relating Dissolution Test Parameters.

1.4.5. Dissolution test apparatus

P) IP apparatus: First is Paddle apparatus (IP) and second is Basket apparatus (IP).

Q) USP apparatus: Apparatus 1 (rotating basket), Apparatus 2 (paddle assembly), Apparatus 3 (reciprocating cylinder), Apparatus 4 (flow-through cell), Apparatus 5 (paddle over disk), Apparatus 6 (cylinder) and Apparatus 7 (reciprocating holder).

USP Dissolution apparatus I (Basket method)

A single tablet is placed in a small wire mesh basket attached to the bottom of the shaft connected to a variable speed motor. The basket is immersed in a dissolution medium (as specified in monograph) contained in a 1000 ml flask. The flask is cylindrical with a hemispherical bottom. The flask is maintained at 37 ± 0.50C by a constant temperature bath. The motor is adjusted to turn at the specified speed and sample of the fluid are withdrawn at intervals to determine the amount of drug in solutions (Figure 5).

 

 

Figure 4: Dissolution Process of Solid Dosage Forms

 

Figure 5: USP Dissolution apparatus I (Basket method)

 

 

USP Dissolution apparatus II (Paddle method)

It is same as apparatus-1, except the basket is replaced by a paddle. The dosage form is allowed to sink to the bottom of the flask before stirring. For dissolution test U.S.P. specifies the dissolution test medium and volume, type of apparatus to be used, rpm of the shaft, time limit of the test and assay procedure for. The test tolerance is expressed as a % of the labeled amount of drug dissolved in the time limit (Figure 6).

 

 

Figure 6: USP Dissolution apparatus II (Paddle method)

 

 

1.4.6. Dissolution testing and interpretation IP standards

Dissolution Testing and Interpretation data was reported in Table 4.Table 4:Dissolution Testing and Interpretation IP Standards

 

 

Sr.no.

Quantity  Stage/level

Number of tablets tested

Acceptance criteria

1

S1

6

Each unit is < D* + 5 percent**

2

S2

6

Average of 12 units (S1 +S2) is equal to or  greater than (> )D, and no unit is less than D - 15 percent**

3

S3

12

Average of 24 units (S1+S2+S3) is equal to or greater  than  (> )D, not more than 2 units are less than d-15 percent** and no unit is less than d-25 percent**

 

*D is the amount of dissolved active ingredient specified in the individual monograph, expressed as a percentage of the labelled content.

** Percentages of the labelled content.

1.4.7. Dosage from conducted dissolution study

A) Immediate release tablet (conventional tablet)

Dissolution apparatus – Type 1 and Type 2 (USP)

Temperature - 37±0.5˚C

Time – 30 min

Time of interval – 5, 10, 15, 20, 25, 30.

Media – PH 1.2 Acidic Buffer, PH 4.5 Acetate buffer, PH 5.8 Phosphate buffer. (depending upon tablet)

Rpm – 75 -100 rpm

Volume – 900 ml

Procedure: The tablet was added into cylindrical vessel containing 1000 ml dissolution media having rpm 75 and tem.37±0.5˚C. Dissolution of tablet was conducted 30 min, in 5 min. of interval, after 5 min particular quantity of sample was removed and analyzed by using suitable analytical technique (U.V. spectroscopy and HPLC).

 

B) Sustained release tablet

Dissolution apparatus – Type 2 (USP)

Temperature -37±0.5˚C

Time – 7 hrs

Media – PH 1.2 Acidic Buffer, PH 6.8 Phosphate buffer.

Rpm – 75 – 100.

Volume – 900 ml.

Procedure - The tablet was added into cylindrical vessel containing 1000 ml PH 1.2 Acidic media having rpm 75 for next two hours and tem. 37±0.5˚C. Dissolution media was changes tablet was added in to PH 6.8 Phosphate buffer for next five hour for 1 hr. of interval. After 1 hr.particular quantity of sample was removed and analyzed by using suitable analytical technique (U.V. spectroscopy and HPLC).

C) Capsule

Dissolution apparatus – Type 2 (USP)

Temperature - 37±0.5˚C

Time – 5 hrs.

Media – PH 1.2 Acidic Buffer, PH 6.8 Phosphate buffer.

Rpm – 75 – 100.

Volume – 900 ml.

Procedure - The Capsule was added into cylindrical vessel containing 1000 ml PH 1.2 Acidic media having rpm 75 for next two hours and tem. 37±0.5˚C. Dissolution media was changes Capsule was added in to PH 6.8 Phosphate buffer for next three hour for 1 hr. of interval. After 1 hr. particular quantity of sample was removed and analyzed by using suitable analytical technique (U.V. spectroscopy and HPLC).

D) Suppositories

Dissolution apparatus – Type 1 (USP)

Temperature - 37±0.5˚C

Time – 60  min

Time of interval – 10, 20, 30, 40, 50, 60.

Media – PH 7.4 Phosphate buffer.

Rpm – 50 – 75 rpm

Volume – 900 ml.

Procedure – The Suppository was added into cylindrical vessel containing 1000 ml dissolution media (PH 7.4 Phosphate buffer) having rpm 75 and tem.37±0.5˚C. Dissolution of Suppository was conducted 60 min, in 10 min. of interval, after 10 min particular quantity of sample was removed and analyzed by using suitable analytical technique (U.V. spectroscopy and HPLC).

2. Non-Official Tests

2.1. Hardness

Tablet requires a certain amount of strength or hardness and resistance to friability to withstand mechanical shocks of handling in manufacture, packaging and shipping. Hardness generally measures the tablet crushing strength (Figure 7).

 

 

 

Figure 7: Hardness Test Apparatus

Importance: To determine the need for pressure adjustments on the tableting machine. Hardness can affect the disintegration. So if the tablet is too hard, it may not disintegrate in the required period of time.  And if the tablet is too soft, it will not withstand the handling during subsequent processing such as coating or packaging.In general, if the tablet hardness is too high, we first check its disintegration before rejecting the batch. If the disintegration is within limit, we accept the batch.If Hardness is high + disintegration is within a time accept the batch.

Factors Affecting the Hardness

Compression of the tablet and compressive force.

Amount of binder. (More binder à more hardness)

Method of granulation in preparing the tablet (wet method gives more hardness than direct method, Slugging method gives the best hardness).

Limits:5 kilograms minimum and 8 kilograms maximum. (Make hardness test on 5 tablets and then take the average hardness).

2.2. Friability

According to U. S. Pharmacopeia, in friability study of tablet with unit mass equal to or less than 650 mg, take a sample of whole tablet corresponding to 6.5 gm. For tablet with unit mass more than 650 mg, take a sample of 10 tablets.Friability of a tablet can determine in laboratory by friability test apparatus. This consist of a plastic chamber that revolves at 25 rpm, for 4 min., dropping the tablets through a Distance of six inches in the friabilator, which is then operate for 100 revolutions (Figure 8).

 

 

Figure 8: Friability Test Apparatus

 

Formula: Initial weight of tablet – weight of tablet after friability / Initial weight of tablet * 100.

Limit: less than 1.0 %.

Evaluation of Precompressional Characteristics of Tabletsor Rheological Characteristics of Granules

1. Particle Size and Shape Determination

Size affects the average weight of tablet, Disintegration Time,     weight variation, friability, flow ability& drying rate.The size & shape depends upon processing requirements & during granulation.The methods for determining size and shape are, 1. Sieving, 2. Sedimentation rate, Microscopy (SEM) and Light Scattering.

2. Surface Area

It is not commonly used for granules but generally used for drug substances.If required particle size is measured and from this surface area is measured.Most method used is gas absorption and air permeability.

A) In gas absorption method: gas is absorbed as monolayer on particles this is in term of calculated and converted to surface area.

B) In air permeability method: the rate of air permeates a bed of powder, is used to calculate surface area of powder sample.

3. Density

Density may influence compressibility, tablet porosity and dissolution.Dense hard granules may require higher load to produce cohesive compact to reduce free granules seen on the surface of tablets.↑ Compressibility ↑ DT, Dissolution, if DT is slower dissolution is indirectly hampered. Dense granules have less friability but cause a problem in releasing the drug. More compressible bed of particulate - less flowable powder or granules. If less dense/compressible - more flowable powder or granules.

Three Methods to determine density

A) Bulk Density

Bulk density is given by equation, ρb = M / Vb

Where, ρb-Bulk density of granules, M -Mass of granules in gm, VbVolume of granules in measuring cylinder in mL.

B) True/tapped density

Tapped/true density is given by equation,

ρt = M / Vt

Where, ρt -Bulk density of granules, M- Mass of granules in gm, VtVolume of granules in measuring cylinder after tapping in mL.

C) Granular density

Intrusion fluid used-Mercury, Any solvent of low surface tension e.g. Benzene. The accuracy of these methods depends upon ability of intrusion fluid to penetrate the pores of granules. Liquids should not masks granules solubilies in it, & having property to penetrate the pores. Density is then determine from volume of intrusion fluid displaced in pycnometer by giving mass of granulation.

It is calculated by using equation, 

Granular Density (D) = M / Vp -Vi

Where, Vp-Total volume of Pycnometer, Vi- Volume of intrusion fluid (mL) containing Mass (gm), M of granules required to fill pycnometer.Granular density was determined by Pycnometer method.

4. Angle of Repose

It is measured by two methods, one is static angle of repose and second is dynamic angle of repose. Various method for determination of angle of repose shown in Figure 9 and Acceptance limits of angle of repose reported in Table 5.

 

 

Table 5: Acceptance limits of angle of repose

Sr. no.

Angle of repose (o)

Type of flow

1

< 25

Excellent

2

25-30

Good

3

30-40

passable

4

> 40

Poor

 

           

Table 6: Acceptance limit Compressibility index

Sr. no.

% Compressibility index

Type of flow

1

5-15

Excellent

2

12-16

Very good

3

18-21

Good

4

23-25

Passable

5

33-38

Poor

6

> 40

Very poor

 

 

 

Figure 9: Method for Determination of Angle of Repose

 

Equation is, tan θ = h/r.

Where, θ - angle of repose, h – height of pile, r – radius of pile.

5. HAUSNER'S RATIO

Hausner’s   ratio was related to interparticulate friction and as such could be used to predict powder flow characteristics. It showed that powder with low particular friction such as coarse sphere had ratio of approximately 1.2, whereas more as cohesiveness- less free flowing powders such as flaks have Hausner’s ratio greater than 1.6.

Formula:Hausner’s ratio: Tapped density / Bulk density

6. Moisture Content

The amount of moisture present in the granule is called moisture content. Generally the granules contain 2 % moisture. It is required for the binding of the powder or granules during compression in die cavity.Percentage of moisture is calculated by using moisture Balance or IR Balance.IR Balance consist of simple balance which is placed I to the casing in which the IR bulb is attached which produce heat inside the chamber. The small amount of sample taken from oven to measure moisture content & place in the moisture balance. Initial reading should be note down after that we are initiated the IR Bulb as IR bulb is initiated the moisture is removed from the granules via heating after that note down the reading.

 

% of moisture is calculated by,

 % moisture content = Initial wt. - Final wt. / initial weight X 100

7. Compressibility Index

It is directly related to the relative flow rate cohesiveness & particle size. It is simple fast and popular method of presiding powder flow characters. It can be obtained from bulk density measurements is the % Compressibility index (C). Acceptance limit Compressibility index was reported in Table 6.

% Compressibility index = Tapped density - Bulk density / Tapped density X 100.

or

I = (1 – V/ Vo) x 100

Where, I – % Compressibility index, V – Volume occupied by powder/ granules after tapping, Vo- volume of powder/granules before tapping.

Conclusion

The QC testing was assigned to production or QC depending on the company base of large scale and small scale. The QC executive was determined the quality tests of the tablets or solid dosage to pass the products into market. They was regularly checked by the RA (Regulatory Affairs) and FDA (Food Drug Administration) bodies.

Acknowledgement
I wish to acknowledge all those who are involved directly or indirectly for compilation of this article. It has been a great honor to work with such a professional.

Conflict of Interest
we declare that we have no conflict of interest.

 

 

 

Bibliography

Savale S. K. 2015. Formulation and Evalution of Diclofenac Sustained Released Tablet. Asian Journal of Pharmaceutical Analysis and Medicinal Chemistry, 3(4): 214 – 225.

Savale S. K. et al., 2016. Formulation and Evaluation of Metformin HCLGastroretentive Floating Sustained Released Tablet. World Journal of Pharmacy and Pharmaceutical Sciences, 5(4): 2456-2466.

Savale S. K. 2016. Formulation and evaluation of metformin HCl micro beads by ionotropic gelation method. Der Pharmacia Lettre, 8 (3): 189-196.

Savale S. K. 2016. Formulation and Evaluation of Gastroretentive Floating Sustained Released Metformin HCl Tablet. International Journal of Medicine and Health Profession Research, 3(1): 17 - 24.

Savale S. K. et al., 2016. Formulation and Evaluation of Gastroretentive Ciprofloxacin HCl Effervescent Tablet. International Journal of Research in Pharmaceutical and Nano Sciences, 5(1): 1 - 8.

Savale S. K. 2016. Formulation and Evaluation of Microspheres with Aceclofenac. World Journal of Pharmaceutical and Medical Research, 2(4): 181-187.

Savale S. K. 2016. Formulation and Evalution of Aceclofenac Sustained Released Tablet. World Journal of Pharmacy and Pharmaceutical Sciences, 5(4): 1394-1405.

Savale S. K. 2017.Formulation and Evaluation of Mouth dissolving buccal film-containing Vildagliptin. Asian Journal of Biomaterial Research, 4(2): 23-38.

Savale S. K. 2017. Quality by Design (QbD) Approach used in Development of Pharmaceutical Formulations. Asian Journal of Biomaterial Research, 3(6): 11-24.

 

 

 

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