In Pharmaceutical Analysis, “Standards” are the backbone of every measurement. To understand them easily, think of a Primary Standard as the “Master Key” and a Secondary Standard as a “Duplicate Key” that we check against the master.
Primary Standard
Primary standards in pharmaceutical analysis are highly pure substances that serve as a reference for quantitative analysis. They are essential for ensuring the accuracy and reliability of analytical methods in the pharmaceutical industry.
Definition:
A primary standard is an extremely pure chemical substance that can be used directly to prepare a solution of known concentration. There is no need to test it against anything else because its purity is guaranteed.
Ideal Characteristics:
- Purity: It should be roughly 99.9% pure.
- Stability: It must be stable at room temperature and should not decompose easily.
- Non-Hygroscopic: It should not absorb moisture from the air (otherwise, its weight will change and the calculation will be wrong).
- High Molecular Weight: This is important to minimize weighing errors during measurement.
- Solubility: It must be easily soluble in the solvent being used.
- Availability: It should be easy to find and inexpensive.
Common Examples:
- For Acid-Base Titrations: Sodium Carbonate (Na2CO3), Potassium Hydrogen Phthalate (KHP).
- For Redox Titrations: Potassium Dichromate (K2Cr2O7), Sodium Oxalate (Na2C2O4).
- For Precipitation Titrations: Silver Nitrate (AgNO3), Sodium Chloride (NaCl).
Secondary Standard
Definition:
A secondary standard is a substance whose concentration is determined by titrating it against a primary standard. These chemicals are not pure enough to be used directly to make a “standard solution.”
Characteristics:
- Less Pure: Compared to primary standards.
- Less Stable: They may react with air, light, or moisture (e.g., NaOH absorbs moisture and CO2 from the air).
- Standardization Required: Its exact concentration must be found by titrating it against a primary standard first.
Common Examples:
- Sodium Hydroxide (NaOH): It is hygroscopic and absorbs CO2 from the air, so it must be standardized using Oxalic Acid or KHP.
- Hydrochloric Acid (HCl): Usually standardized against Sodium Carbonate.
- Potassium Permanganate (KMnO4): It is unstable and must be standardized using Sodium Oxalate.
Significance of Primary and secondary standards
In the pharmaceutical field, standards are more than just laboratory chemicals. They serve as the legal and scientific benchmarks that guarantee the safety and effectiveness of every medication. Their importance can be summarized in following key areas:
Standardization of Working Solutions:
In the testing laboratories, using expensive Primary Standards for every single test is not cost-effective. Labs create Secondary Standards (also called Working Standards) and “verify” its strength using a Primary Standard (a process called Standardization). Then it is used for the rest of the routine testing. Example: A lab standardizes Sodium Hydroxide (NaOH) against Potassium Hydrogen Phthalate (Primary Standard) and is used to test hundreds of samples of acidic drugs.
Calibration:
Modern pharmacy relies on complex machines like HPLC (High-Performance Liquid Chromatography) or UV-Spectrophotometers. Standard solutions are used to calibrate analytical instruments, ensuring that measurements are accurate and reliable.
Validation:
They help confirm that analytical methods consistently produce precise and accurate results. Example: When developing a new method to measure the concentration of an active pharmaceutical ingredient (API) in a tablet, a primary standard such as Potassium Hydrogen Phthalate (KHP) is used to validate the method. By repeatedly analysing solutions of known concentration prepared from the primary standard, the laboratory can demonstrate that the method yields accurate and reproducible results.
Quality Control:
Standards are essential for maintaining the consistency and quality of pharmaceutical products, ensuring each batch meets required specifications. These are used in the pharmaceutical industry to check the purity of raw materials.
Regulatory Compliance:
Primary standards play a vital role in fulfilling the requirements set by pharmacopeias (IP, BP, USP), as they offer the necessary reference materials to ensure that pharmaceutical analyses are precise and traceable. For instance, during the drug approval process, regulatory bodies like the FDA mandate that all analytical methods employed for quality testing must be validated with primary standards. This process underpins the safe approval and ongoing monitoring of pharmaceutical products.
Comparison Table
| Property | Primary Standard | Secondary Standard |
| Purity | Extremely High (Reference grade) | Less pure (Working grade) |
| Preparation | Direct weighing and dilution | Standardization via titration |
| Atmospheric Stability | High (Does not absorb moisture) | Low (Hygroscopic/ Deliquescent) |
| Usage | Used to standardize others | Used for routine laboratory analysis |
| Examples | Sodium Carbonate (Na2CO3), Potassium Hydrogen Phthalate (KHP) | Sodium Hydroxide (NaOH), Hydrochloric Acid (HCl) |
Standardization of 0.1 N NaOH
The Objective: To determine the exact normality of a 0.1 N Sodium Hydroxide (NaOH) solution (Secondary Standard) using Oxalic Acid (Primary Standard).
5.1. Requirements
- Primary Standard: Oxalic Acid (H2C2O4⋅2H2O)
- Secondary Standard: Sodium Hydroxide (NaOH)
- Indicator: Phenolphthalein
- Endpoint: Colorless to Permanent Pale Pink
5.2. Preparation of Primary Standard (0.1 N Oxalic Acid)
Since Oxalic Acid is a primary standard, we prepare it by direct weighing.
- Equivalent Weight of Oxalic Acid: Oxalic acid is a dicarboxylic acid (H2C2O4⋅2H2O), meaning it has two replaceable hydrogen (H+) ions.
(COOH)2 → (COO–)2 + 2H+ . Its basicity is 2.
Equivalent Weight = Molecular Weight/ n-factor (Basicity)
Equivalent Weight = 126.06 /2 = 63.03g
- Formula: To make 1000 ml of 1 N, we need 63 g.
- Therefore, to make 100 ml of 0.1 N, weigh exactly 0.63 g and dissolve it in 100 ml of distilled water.
5.3. Procedure
- Fill the Burette: Wash and rinse the burette with NaOH solution, then fill it to the zero mark.
- Pipette out: Transfer 10 ml of the 0.1 N Oxalic Acid into a clean conical flask.
- Add Indicator: Add 2–3 drops of Phenolphthalein. The solution remains colorless (because it is acidic).
- Titrate: Add NaOH dropwise from the burette while swirling the flask.
- Endpoint: Stop when a single drop turns the solution pale pink that persists for at least 30 seconds.
- Record: Note the volume of NaOH used (V2).
5.4. Calculation
Using the normality equation: N1V1(Oxalic Acid) = N2V2 (NaOH)
N1 = 0.1 N; V1 = 10 ml; V2 = Burette reading (let’s say 10.2 ml); N2 =?
N2 = 0.1 × 10 / 10.2 = 0.0980 N
5.5. Why do we do this?
The label on the bottle might say “0.1 N NaOH,” but because NaOH is a secondary standard, it starts absorbing moisture the moment the bottle is opened. By doing this titration, you found that the “true” strength is actually 0.0980 N. Now use this “true” value for all subsequent drug assays.