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Tablets & Capsules September 2020 45 to develop a calibration curve with an associated equation. The equa- tion can then be used to predict the API concentration in samples not belonging to the calibration set. Validation can be internal or external. Internal validation esti- mates the reproducibility of a developed model and avoids over-interpretation of data. This can be performed using cross-val- idation techniques such as che- mometrics or leave-one-out val- idation, among others. External validation is performed using external samples that do not belong to the calibration set. Using HPLC to determine the concentration of two APIs in soft gelatin capsules requires the development of a different method for each API, which consumes more materials and time than using a single NIR-chemometrics method to predict the concentration of both APIs [5]. The following study describes the development of an NIR-chemometrics which require additional reagents, supplies, and time for sample preparation [1]. NIR is based on molecular vibrations generated when inci- dent radiation (commonly from a halogen lamp with a tungsten filament) interacts with matter and stretches or bends the mate- rial's molecular bonds. Stretching refers to increases and decreases in bond length, while bending refers to changes in the angle between molecular bonds [2]. This interac- tion between radiation and matter produces an analytical response known as a spectrum, which can be detected using a lead sulfide (PbS) detector. For NIR spectroscopy, this spectrum is the result of a combination of bands and overtones from fundamental molecular vibrations. These overtones occur at frequen- cies between 12,500 and 4,000 cm -1 , which is roughly two to three times the frequency of fundamental vibra- tions, which are detected using mid-IR spectroscopy. The hydrogen bonds OH, CH, and NH are band absorptions frequently observed in NIR spectra [2]. NIR has been implemented in many stages of the manufacturing process, but little information is avail- able about applying this method to soft gelatin capsules (softgels). A softgel is a solid dosage form consisting of a hydrophilic or lipophilic fill formulation containing one or more APIs hermetically sealed inside a one-piece gelatin shell. Softgels are widely used to improve the bio- availability of poorly water-soluble and poorly permeable APIs, to improve content uniformity of low-dose drug products, and to enhance patient adherence by masking unpleasant scents and tastes [3, 4]. Determining the API content in softgels is commonly done using conventional techniques such as HPLC. However, analyzing two APIs in a softgel increases the complexity, making conventional analysis difficult. Mid-IR spectra allow the identification of samples by comparing the sample spectra with standard spectra. However, because NIR spectra are not as structurally selective as mid-IR spectra, chemometric techniques such as multivariate analysis can be applied to the NIR spectra data to extract chemical information and increase analyte selectivity. NIR model development To develop an NIR quantification method requires two principal steps: calibration and validation. Calibra- tion involves preparing samples for a calibration set with changes to the interesting variable. If the interesting variable is API concentration, a design experiment would be applied to obtain samples with lower and higher API concentrations with reference to a target concentration Formulation Ibuprofen Caffeine g Ibu/g % g Caf/g % Target 0.6154 100.00 0.1000 100.00 01 0.6155 100.02 0.0000 0.00 02 0.0000 0.00 0.2599 259.90 03 0.4922 79.98 0.0500 50.00 04 0.5538 89.98 0.2001 200.07 05 0.5848 95.02 0.0800 80.03 06 0.6153 99.99 0.1199 119.93 07 0.6461 104.99 0.1500 150.01 08 0.6770 110.02 0.0951 95.08 09 0.7383 119.98 0.0900 90.00 10 0.7077 115.01 0.1100 110.03 11 0.6153 99.98 0.1050 105.00 12 0.5538 89.99 0.1500 150.03 13 0.0000 0.00 0.0000 0.00 14 0.6154 100.01 0.0999 99.88 15 0.3077 50.01 0.1001 100.12 Table 1 Pharmaceutical formulations prepared at laboratory scale NIR is based on molecular vibrations generated when incident radiation (commonly from a halogen lamp with a tungsten filament) interacts with matter and stretches or bends the material's molecular bonds.