Development of 3D Printed Variable Dose Multi-Drug Tablets Containing Metformin, Sitagliptin, and Simvastatin by Selective Laser Sintering and their Simultaneous Quantification Using a Novel HPLC Method

Hypertension remains one of the most prevalent chronic non-communicable diseases worldwide and is a major contributor to cardiovascular morbidity and mortality. Sustained elevation of blood pressure induces structural and functional alterations in the vasculature, including arterial stiffening and reduced vascular elasticity, which ultimately compromises tissue perfusion and organ function [1]. The increased hemodynamic load forces the heart to work against elevated vascular resistance, resulting in left ventricular hypertrophy, myocardial ischemia, angina, and, over time, heart failure. In addition to cardiovascular complications, hypertension is a leading cause of chronic kidney disease, while diabetic patients are particularly susceptible to the development of hypertension and its associated complications [2, 3].

Despite the availability of numerous antihypertensive therapies, approximately 70% of patients fail to achieve the recommended target blood pressure of <140/90 mmHg with monotherapy [4]. Long-term studies indicate that most patients require an average of three antihypertensive agents to attain adequate blood pressure control [5]. Because hypertension is driven by multiple physiological pathways, combination therapy offers greater efficacy than monotherapy by targeting several mechanisms simultaneously [5, 6]. However, treatment adherence remains a major challenge, particularly in patients with multiple comorbidities and complex medication regimens [7]. Single-pill combination therapies have therefore emerged as an important strategy to reduce pill burden and improve adherence [5].

Current first-line antihypertensive treatment relies primarily on calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and diuretics [6,8,9]. Clinical evidence demonstrates that combining antihypertensive agents from complementary pharmacological classes produces substantially greater blood pressure reductions than escalating the dose of a single agent, while reducing dose-related adverse effects [10, 11]. Consequently, fixed-dose combinations (FDCs) and single-pill combinations (SPCs) have become widely accepted therapeutic approaches for hypertension management [12]. Examples include ARB/diuretic combinations, which counteract compensatory activation of the renin–angiotensin system and reduce diuretic-associated hypokalemia [13-15], and ARB/CCB or ACE inhibitor/CCB combinations, which improve cardiovascular outcomes while minimizing CCB-induced peripheral edema [16, 17].

Although commercially available FDCs provide important benefits, they are inherently limited by their fixed strengths and compositions. These products are designed for average patient populations and therefore provide limited flexibility for individualized dose adjustment according to patient-specific characteristics, disease severity, treatment response, and comorbidities [18]. Such limitations highlight the growing need for precision medicine approaches that tailor pharmacotherapy to individual patient requirements.

Precision medicine seeks to optimize therapeutic outcomes by integrating patient-specific factors, including genetics, disease characteristics, lifestyle, and environmental influences, into clinical decision-making [19, 20]. In hypertension management, this approach creates opportunities to customize drug combinations, doses, and release profiles according to individual therapeutic needs [21]. Conventional pharmaceutical manufacturing, however, is poorly suited to produce personalized dosage forms on demand. Traditional dose-adjustment strategies such as tablet splitting often result in significant variability in tablet mass and drug content, thereby compromising dosing accuracy and therapeutic reliability [5, 22-24]. For precision medicine to be effective, the tablets need to be easily fabricated, customizable, and highly affordable which would encourage widespread usage and allow it to be fabricated on the spot after diagnosis. [22].

Three-dimensional (3D) printing has emerged as a transformative technology capable of addressing these challenges by enabling the fabrication of patient-specific dosage forms directly from digital designs [5, 25, 26]. Through precise control of tablet geometry, drug loading, and internal structure, 3D printing facilitates the production of individualized medicines with tailored drug release profiles and multidrug combinations. Such personalized polypills have the potential to improve medication adherence, reduce pill burden, minimize adverse effects, and enhance therapeutic outcomes in patients with hypertension [27-29]. Several 3D-printing technologies have been explored for pharmaceutical applications, including fused deposition modeling (FDM), binder jetting, stereolithography (SLA), semi-solid extrusion, and selective laser sintering (SLS) [25, 26, 30]. However, FDM often requires high processing temperatures and drug-loaded filament preparation, potentially limiting the incorporation of thermosensitive drugs. Binder jetting requires liquid binders and additional post-processing steps, while SLA depends on photopolymerizable materials that may present formulation and regulatory challenges [25, 26, 30]. Among these technologies, Selective Laser Sintering (SLS) offers several distinct advantages for the fabrication of personalized multidrug tablets. SLS employs a laser to selectively fuse powder particles in a layer-by-layer manner, enabling the production of dosage forms with high precision, excellent reproducibility, and complex internal architectures. Unlike FDM, SLS does not require filament preparation, thereby simplifying formulation development and expanding the range of compatible pharmaceutical excipients. The technology also enables precise modulation of tablet porosity, density, drug loading, and release behavior while minimizing material waste and supporting rapid, small-batch production [25, 26, 30]. In addition, its solvent-free process and ability to incorporate multiple active pharmaceutical ingredients (APIs) within a single dosage form make SLS particularly suitable for the development of personalized antihypertensive polypills. The ability of SLS technology to produce individualized combination products directly addresses one of the major shortcomings of conventional FDCs: the lack of dosing flexibility. For hypertensive patients requiring multiple agents at personalized dose strengths, SLS provides a practical platform for the on-demand manufacture of patient-centric dosage forms that align with the principles of precision medicine [19-21].

Despite the growing interest in pharmaceutical 3D printing and the demonstrated clinical benefits of antihypertensive combination therapy, the integration of these two fields remains largely unexplored. Most reported studies on 3D-printed oral dosage forms have focused on single-drug systems or proof-of-concept formulations, whereas relatively few investigations have addressed the development of personalized multidrug antihypertensive tablets capable of simultaneously delivering clinically relevant drug combinations at individualized dose strengths. Furthermore, although Selective Laser Sintering (SLS) has emerged as a promising platform for manufacturing highly customizable solid dosage forms, limited information is available regarding its application for producing patient-centric antihypertensive polypills that combine the therapeutic advantages of fixed-dose combinations with the flexibility required for precision medicine. Consequently, a significant gap exists between the clinical demand for individualized antihypertensive therapies and the availability of robust manufacturing approaches capable of delivering customized multidrug dosage forms in a practical and scalable manner. Addressing this gap is essential for translating the concept of precision cardiovascular pharmacotherapy from a theoretical framework into a clinically applicable reality. 

Thus, the rationale of the present study is to integrate the established clinical benefits of antihypertensive combination therapy with the flexibility of personalized medicine through the application of selective laser sintering based 3D printing technology. SLS was selected because of its high resolution, formulation versatility, solvent-free processing, compatibility with multiple APIs, and suitability for small-scale, on-demand pharmaceutical manufacturing. The objective of this study is to develop and evaluate personalized multidrug antihypertensive tablets fabricated using SLS 3D printing, thereby establishing a platform for next-generation patient-centric management of hypertension. 

MATERIALS AND METHODS

Materials

Valsartan, hydrochlorothiazide, and amlodipine besylate were purchased from Biosynth International, Inc. (KY, USA). Kollidon VA 64 and Kollidon VA 64 fine were obtained from BASF Corporation (NY, USA). Crospovidone, microcrystalline cellulose (MCC), sodium starch glycolate, and croscarmellose sodium were obtained from JRS Pharma (NY, USA). Mannitol, polyethylene oxide, ammonium acetate, FD&C Red #3, FD&C Red #40, FD&C Yellow #6, and FD&C Blue #3 were purchased from Fischer Scientific (MA, USA). Acetonitrile (HPLC grade), and methanol (HPLC grade) was purchased from VWR International (PA, USA). Candurin®  Gold Sheen was provided as a free sample by EMD Performance Materials Corp. (Germany).

Excipient Compatibility

Physical mixtures of valsartan, hydrochlorothiazide, amlodipine besylate, and excipients were prepared in a 1:1 ratio, mixed for 5 minutes in a mortar and pestle to ensure homogeneity, and 5–10 mg samples were subjected to differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). DSC was performed using DSC25 (TA Instruments) where samples (5–10 mg) were placed in T₀ aluminum pans, sealed, and heated at 10°C/min under a nitrogen purge (50 mL/min) from 25°C to 400°C. Thermograms were analyzed for melting or decomposition onset using TRIOS software. TGA (TGA55, TA Instruments) was conducted on 5–10 mg samples in aluminum crucibles, heated at 10°C/min under a nitrogen purge (50 mL/min) from 25°C to 400°C. Thermal degradation profiles were analyzed using TRIOS software.

Simultaneous Determination of Valsartan, Hydrochlorothiazide, Amlodipine besylate

A comprehensive review of the literature revealed several reported high-performance liquid chromatography (HPLC) methods for the quantitative determination of amlodipine, valsartan, and hydrochlorothiazide, either as individual drug substances or in various fixed-dose combination products [31-36]. However, differences in chromatographic conditions, analytical objectives, and formulation characteristics necessitated the development of a robust method capable of the simultaneous determination of all three drugs in the present study.

Chromatographic analyses were performed using a Waters e2695 HPLC system (Waters Corporation, Milford, MA, USA) equipped with a 2489 UV/Visible detector and controlled through Empower™ chromatography software. Analytical-grade ammonium acetate, acetonitrile, and methanol were used throughout the study. All reagents and solvents employed for method development and validation were of analytical grade. Method development was conducted through a systematic optimization process to achieve satisfactory separation, peak symmetry, and resolution of hydrochlorothiazide, valsartan, and amlodipine besylate. Several chromatographic parameters were investigated, including the composition of the mobile phase, the ratio of organic solvent to aqueous buffer, and other chromatographic conditions such as flow rate, detection wavelength, and column operating conditions. Multiple experimental trials were performed to identify the optimal conditions that provided adequate retention, high resolution, and reproducible peak characteristics for all analytes. Finally, chromatographic separation was achieved on a Phenomenex Luna C18(2) 100 Å column (Phenomenex, Torrance, CA, USA, 150 x 4.6 mm, 5 µm) maintained at 30 ⁰C. The mobile phase consisted of ammonium acetate buffer (30 mM, neutral pH, solution A) and a mixture of methanol and acetonitrile in the volume ratio of 80:20 (solution B) with a flow rate of 1.2 mL/min and injection volume of 10 µL. Detection was performed at 235 nm. Following optimization, a gradient elution method (Table 1) suitable for the simultaneous determination of hydrochlorothiazide, valsartan, and amlodipine besylate was established and subsequently validated.

Standard solutions were prepared by dissolving 5 mg of each drug in 10 mL of diluent (mixture of methanol and ammonium acetate buffer with volume ratio of 70:30), followed by serial dilutions to obtain 100 µg/mL stock solution of each drug. Accurately measured aliquots from the stock standard solutions of valsartan, hydrochlorothiazide and amlodipine besylate were transferred into sets of 10 mL volumetric flasks and diluted to volume with the diluent to prepare concentration ranges of 1.56  – 100 µg/mL. Concentration values were then plotted against area under the peak (AUP) values. Mobile phase A was prepared by dissolving 2.31 g of ammonium acetate (30mM) in 1000 mL deionized water. Solution was then filtered with 0.45 µm membrane filter (MilliporeSigma, MA, USA).

Table 1 Gradient flow conditions for the optimized HPLC method

3D Printing of Placebo Tablets

Powder blends were prepared by individually passing all formulation components through a #40 mesh sieve to ensure uniform particle size distribution. The sieved materials were then blended manually using a mortar and pestle until a homogeneous mixture was obtained. The resulting powder blend was subsequently re-sieved through a #40 mesh to break down any agglomerates formed during mixing and to further improve blend uniformity, which is critical for consistent powder spreading and processing during Selective Laser Sintering (SLS) 3D printing. All formulation constituents were incorporated based on their respective % w/w composition.

Placebo formulations containing Kollidon® VA 64 (70–80% w/w), Kollidon® VA 64 Fine (5–15% w/w), Crospovidone (3% w/w), and different colorants, including FD&C Red #3, FD&C Red #40, FD&C Yellow #6, FD&C Blue #3, and Candurin® Gold Sheen, were evaluated for their suitability in SLS based 3D printing. Crospovidone was incorporated as a superdisintegrant to promote rapid tablet disintegration, while the colorants were included as laser energy absorbers to enhance the sintering process. Among the various formulations investigated, the formulation composition shown in Table 2, containing Kollidon® VA 64 (80% w/w), Kollidon® VA 64 Fine (13% w/w), FD&C Red #3 (5% w/w), and Crospovidone (3% w/w) demonstrated the most favorable printing performance and tablet characteristics.

Table 2 Final formulation composition for placebo tablets

Tablet designs (10 mm diameter × 5 mm height) were created using Tinkercad® software and exported as stereolithography (.STL) files to Sintratec Central. A 150 g powder batch of the optimized formulation (Table 2) was prepared and loaded into SLS 3D  printer reservoir (Sintratec Kit, 3D Chimera, Miami, FL, USA). Prior to printing, the powder bed was preheated to facilitate the sintering process. Printing parameters were optimized by evaluating chamber and powder surface temperatures ranging from 80°C to 110°C and laser scanning speeds between 150 and 300 mm/s. Following optimization, powder surface and chamber temperatures were set at 110 °C and 95 °C respectively. Laser scanning speed of 150 mm/s was found to be most suitable. After printing, the tablets were allowed to cool for 30–45 min before removal from the powder bed and recovery of the printed tablets by removing excess unsintered powder. Average tablet weight was determined using an electronic analytical balance, while tablet diameter and thickness were measured using a digital vernier caliper. The 3D printed placebo tablets were stored at room temperature in scintillation vials for further evaluation.

3D Printing of Multi-Drug Combination Tablets

Multi-drug combination tablets were fabricated using optimized process parameters established for placebo formulations. Formulations containing lower doses (F1) and higher doses (F2) shown in Table 3, respectively were designed based on the minimum dose requirements of the three drugs [37-40].

Figure 1 DSC thermograms showing compatibility of valsartan with various excipients, A) Melting endotherm of pure valsartan.

Figure 2 DSC thermograms showing compatibility of hydrochlorothiazide with various excipients, A) Melting endotherm of hydrochlorothiazide.

Figure 3 DSC thermograms showing compatibility of amlodipine besylate with various excipients, A) Melting endotherm of pure amlodipine besylate.

Figure 4 TGA graph of A) Valsartan, B) Hydrochlorothiazide, and C) Amlodipine besylate. D) DSC thermogram of formulation F11 showing onset of melting temperature at 73°C and a peak melting temperature of 88°C.

Figure 5 HPLC chromatogram of combination of hydrochlorothiazide, valsartan and amlodipine besylate at a wavelength of 235 nm and concentration of 100 µg/mL.

Figure 6 SLS based 3D printing process. A) Powder spreading via the coater, and B) Powder sintering via laser resulting in tablet formation.

Figure 7 SLS based 3D printed tablets. A) Placebo tablets, B) Tablets in a scintillation vial, and C) Diameter of tablets as measured by vernier calipers.

(A)

(B)

Figure 8 Drug release profiles from SLS 3D printed tablets at 37 ⁰C (data presented as mean ± SD, n = 6). Cumulative drug release from (A) Formulation F17, and (B) Formulation F22.

(A)

(B)

Figure 8 Drug release profiles from compressed tablets at 37 ⁰C (data presented as mean ± SD, n = 6). Cumulative drug release from (A) Formulation F23, and (B) Formulation F24.

Figure 9 Drug release profile from compressed tablets at 37 ⁰C from formulation F25(data presented as mean ± SD, n = 6).

In contrast, formulations F23 and F25 exhibited lower amlodipine besylate dissolution, with final releases of approximately 13.1% and 18.1%, respectively. Valsartan release was rapid and extensive in all formulations, with F23 and F25 achieving near-complete dissolution within 60 min, whereas F24 reached approximately 93.7% release after 120 min.

DISCUSSION

Three-dimensional (3D) printing has emerged as a promising manufacturing platform for personalized medicines, enabling the production of dosage forms with patient-specific strengths, drug combinations, and release characteristics. Among the available additive manufacturing technologies, selective laser sintering (SLS) offers several advantages for pharmaceutical applications, including solvent-free processing, single-step fabrication, high printing precision, rapid production, and the ability to manufacture complex dosage forms while minimizing drug degradation. These attributes have established SLS as one of the most promising technologies for personalized oral drug delivery systems [48, 49].

Preformulation studies demonstrated that all investigated excipients were compatible with hydrochlorothiazide, valsartan, and amlodipine besylate, with the exception of mannitol. Thermal analysis revealed a decrease in melting temperature and broadening of melting endotherms when mannitol was combined with hydrochlorothiazide or amlodipine besylate, suggesting potential solid-state interactions. Mannitol has previously been reported to influence drug stability through crystallization-induced changes in water activity within amorphous regions of formulations, which can promote degradation of susceptible drug substances [50-53]. Consequently, mannitol was excluded from further formulation development. Because successful SLS printing requires a thermally responsive excipient capable of promoting particle fusion below the degradation temperatures of the incorporated drugs, Kollidon® VA 64 was selected as the primary binder. The melting temperature of Kollidon® VA 64 (~91°C) was lower than those of hydrochlorothiazide, amlodipine besylate, and valsartan, making it suitable for facilitating laser-induced fusion while minimizing drug degradation. Similar use of copovidone-based polymers in SLS printing has been reported previously due to their excellent printability and binding characteristics [54, 55].

A gradient HPLC method capable of simultaneously quantifying hydrochlorothiazide, valsartan, and amlodipine besylate was successfully developed. Initial attempts based on published methods [31, 33, 36, 56] were unable to achieve adequate separation because of the considerable differences in physicochemical properties and USP analytical conditions for the three drugs. The optimized gradient method employed a more aqueous initial mobile phase to facilitate elution of the hydrophilic hydrochlorothiazide, followed by an increase in organic content to elute the more lipophilic valsartan and amlodipine besylate. This approach enabled reliable quantification of all three drugs in a single analytical run.

Optimization of SLS process parameters revealed that tablet quality was highly dependent on printing temperature, laser scanning speed, and formulation composition. For placebo tablets, successful fabrication was achieved at a chamber temperature of 95°C, surface temperature of 110°C, and scanning speed of 150 mm/s. Previous studies have shown that laser energy input and scanning speed significantly influence powder fusion, porosity, mechanical strength, and dissolution performance of SLS-printed dosage forms [41, 44, 57]. Consistent with these reports, higher scanning speeds likely reduced the time available for particle fusion, whereas lower speeds promoted more effective sintering and tablet formation.

Although these conditions produced acceptable placebo tablets, formulation F11 could not be printed successfully because the powder blend solidified before proper spreading. DSC analysis revealed an onset melting temperature of 73°C and a melting peak at 88°C, substantially lower than the temperatures used for placebo printing. The reduced thermal transition likely resulted from interactions between valsartan and Kollidon® VA 64, both of which possess relatively low melting temperatures. Adjustment of the chamber and surface temperatures ultimately led to successful fabrication of F13 at 65°C and 95°C, respectively. However, the tablets exhibited excessive hardness and compactness. Increasing crospovidone concentration and maintaining 5% FD&C Red Dye No. 3 yielded formulation F17, which showed acceptable mechanical integrity and handling characteristics. When valsartan loading was increased in F21, tablet hardness increased further, necessitating formulation optimization through higher crospovidone content and a lower surface temperature, resulting in formulation F22.

Drug-content analysis demonstrated acceptable assay values for all formulations, indicating that neither SLS processing nor conventional compression adversely affected drug loading. The assays obtained for the 3D-printed tablets (F17 and F22) and compressed tablets (F23–F25) were within pharmacopeial acceptance limits, confirming the robustness of both manufacturing approaches.

The dissolution studies highlighted substantial differences between the 3D-printed and compressed formulations. Formulation F17 achieved 60-min releases of approximately 71% hydrochlorothiazide, 93% valsartan, and 60% amlodipine besylate, whereas F22 exhibited significantly lower releases of approximately 40%, 49%, and 23%, respectively. The reduced dissolution observed for F22 is likely attributable to its higher valsartan content, which increased matrix densification through enhanced fusion with Kollidon® VA 64 during sintering. SLS processing is known to produce amorphous or partially fused polymeric matrices, and increasing polymer-drug interactions can reduce porosity and water penetration, thereby slowing drug release [41, 55, 58].

Evidence also suggested that FD&C Red Dye No. 3 contributed to altered dissolution behavior. DSC analysis showed shifts in the valsartan melting endotherm and the appearance of exothermic events for hydrochlorothiazide and amlodipine besylate, indicating possible drug–dye interactions. To explore this hypothesis, single-punch compressed tablets were prepared. Formulation F23, which contained dye but did not undergo thermal processing, showed substantially higher valsartan release than F22, suggesting that thermal fusion between valsartan and Kollidon® VA 64 played a major role in the slower dissolution of the 3D-printed tablets. More importantly, elimination of the dye in F24 resulted in markedly improved release of hydrochlorothiazide and amlodipine besylate, further supporting the possibility of drug–dye interactions affecting dissolution performance. This observation was reinforced by formulation F25. Despite rapid tablet disintegration, attributable to the inclusion of microcrystalline cellulose and sucrose, hydrochlorothiazide and amlodipine besylate still exhibited relatively poor dissolution. If disintegration was the sole limiting factor, improved dissolution would have been expected. Therefore, the persistence of reduced drug release despite rapid tablet breakup suggests that interactions involving FD&C Red Dye No. 3 may have influenced drug solubility or wettability, particularly for hydrochlorothiazide and amlodipine besylate. Additional solid-state characterization techniques such as PXRD, FTIR, Raman spectroscopy, and hot-stage microscopy would be valuable in future studies to elucidate the nature of these interactions.

Overall, the study demonstrates the feasibility of producing variable-dose combination tablets containing hydrochlorothiazide, valsartan, and amlodipine besylate using SLS 3D printing. Printing performance and drug release were strongly influenced by formulation composition and process parameters. Formulation F17 provided the most favorable balance between printability, mechanical strength, drug content uniformity, and dissolution performance. The findings further highlight the importance of excipient selection and excipient-drug interactions in the development of SLS-manufactured multi-drug dosage forms and support the continued application of SLS technology for personalized cardiovascular therapies.

CONCLUSION

This study successfully demonstrated the feasibility of utilizing selective laser sintering (SLS) 3D printing to fabricate personalized multi-drug antihypertensive tablets containing hydrochlorothiazide, valsartan, and amlodipine besylate at variable dose strengths. A novel gradient HPLC method was developed and validated for the simultaneous quantification of all three drugs, providing a robust analytical tool for formulation development and quality assessment.

Preformulation studies established the compatibility of the selected drugs with most investigated excipients, while identifying mannitol as unsuitable because of potential interactions with hydrochlorothiazide and amlodipine besylate. Optimization of formulation composition and printing parameters revealed that successful fabrication of multi-drug tablets depended strongly on thermal properties of the powder blend, dye concentration, and disintegrant level. The optimized formulations (F17 and F22) were successfully printed with acceptable physical characteristics and drug content uniformity, demonstrating the capability of SLS technology to produce individualized fixed-dose combination products.

Dissolution studies showed that drug release behavior was significantly influenced by formulation composition and processing conditions. Formulation F17 exhibited the most favorable overall performance, achieving substantially higher drug release than F22, while comparison with conventionally compressed tablets highlighted the influence of SLS-induced fusion and potential interactions involving FD&C Red Dye No. 3 on dissolution characteristics. The improved release observed in dye-free compressed tablets suggests that further investigation of dye–drug interactions is warranted to optimize formulation performance.

Overall, the findings demonstrate that SLS 3D printing is a promising platform for the manufacture of personalized cardiovascular polypills capable of delivering multiple antihypertensive agents within a single dosage form. The technology offers flexibility in dose customization, supports the goals of precision medicine, and has the potential to improve patient adherence by reducing pill burden. Future studies should focus on detailed solid-state characterization, optimization of excipient selection, and evaluation of long-term stability and scalable manufacturing approaches to facilitate the clinical translation of personalized SLS-printed multi-drug tablets.

DECLARATION OF COMPETING INTEREST

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

ACKNOWLEDGEMENTS

Financial support for this project was provided by the School of Pharmacy at the Massachusetts College of Pharmacy and Health Sciences as well as Massachusetts Life Sciences Center-Capital Grants.

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